32.14: Part 3 - Climate Change, Infectious Disease and Pandemics

Written by Henry Jakubowski

Learning Goals

(Learning goals written by Claude, Anthropic)

By the end of this chapter, students should be able to:

Historical Pandemics and Key Pathogens

• Describe the scale and mortality of major historical pandemics and explain how each arose from a pathogen jumping from an animal reservoir to an immunologically naive human population, using COVID-19, the 1918 influenza, the Black Death, measles, malaria, and tuberculosis as examples.
• Explain how the Y. pestis plasminogen activator (Pla) uses a His/Asp/water catalytic mechanism — distinct from the Ser-His-Asp triad of serine proteases — to cleave plasminogen to plasmin, dissolving fibrin clots to spread infection, and explain why reduced pPCP1 plasmid copy number lowered virulence in later plague epidemics.
• Explain how measles emerged from rinderpest, why a minimum host population of 250,000–500,000 is required for self-sustained transmission, and how molecular clock phylogenetics of RNA sequences placed measles emergence at the 6th century BCE.

Influenza Host Specificity and Pandemic Risk

• Explain how influenza's segmented ssRNA genome enables antigenic drift (error-prone RNA polymerase) and antigenic shift (segment reassortment during co-infection), and explain why the ongoing H5N1 avian influenza pandemic poses a future pandemic risk.
• Explain why avian influenza binds Sia α(2,3)Gal while human strains bind Sia α(2,6)Gal on host N-linked glycoproteins, and explain how the single D225G substitution eliminates the K222–D225 salt bridge, gains dual receptor specificity, increases binding affinity (KD drops from 13.7 to 4.73 μM for 18H1), and enables deeper lung binding.
• Interpret surface plasmon resonance KD, kon, and koff data for wild-type and D225G mutant hemagglutinins binding Sia α(2,6)Gal and Sia α(2,3)Gal, and explain what changes in kon versus koff account for the observed affinity differences.

Zoonotic Disease, Climate Change, and Emerging Pathogens

• Define zoonosis and vector-borne disease, identify the six anthropogenic factors that increase animal-to-human pathogen spillover risk, and use the diclofenac/vulture collapse (COX-2 inhibition → 90% vulture decline → ~100,000 excess human deaths/year, $70 billion/year economic cost) as a case study in cascading biodiversity effects.
• Explain how thawing permafrost threatens human health through anthrax spore release, revival of dormant ancient organisms, and emergence of novel viruses to which modern humans have no immunity, and describe four fungal pathogens (Candida auris, Cryptococcus deuterogattii, Coccidioides immitis, Puccinia striiformis) expanding with climate warming.

Bats, Inflammasomes, and Pandemic Risk

• Explain the two-signal model of NLRP3 inflammasome activation — Signal 1 (PAMP/TLR/NF-κB → pro-IL-1β and NLRP3 transcription) and Signal 2 (DAMP/NLR/ATP/K⁺ efflux → caspase-1 activation → IL-1β/IL-18 cleavage and release) — and explain why this two-signal requirement limits excessive inflammation.
• Explain how bats suppress NLRP3 inflammasome signaling at multiple levels — reduced PAMP/DAMP recognition, decreased NLRP3 RNA splicing, altered LRR domain, caspase-1 inhibition, and IL-1β proteolytic degradation — connect elevated bat flight temperatures (~39.6°C) to reduced viral pathogenicity, and predict how climate-driven habitat shifts in Southeast Asia increase pandemic spillover risk.

 

Introduction

Microorganisms can cause acute and chronic diseases that, if left untreated, can lead to death.  Infections with the Human Papillomavirus (HPV) can cause cancer of the cervix, vagina, vulva, penis, anus, and throat.  Modern vaccines against HPV can prevent over 90% of these cancers.  The bacteria H. pylori can, in some people, cause stomach illness (such as severe chronic gastritis and ulcers), which can lead to stomach cancer.  The Coxsackie virus, through binding to receptors on cardiac myocytes, can cause heart disease (acute myocarditis and cardiomyopathy) and ultimately death. 

Acute microbial diseases can cause epidemics and pandemics (worldwide epidemics).  Everyone has experienced the COVID-19 pandemic caused by the SARS-CoV-2 coronavirus.  Johns Hopkins estimates, as of 3/10/23 (end of their data collection), that there were about 677 million reported cases of COVID-19 and about 6.9 million deaths. The WHO estimates that, for the first two years of the pandemic (2020 and 2021), there were 14.83 million excess deaths globally, 2.74 times the number of reported virus deaths (5.42 million).  Machine learning models suggest that there have been more than 20 million excess deaths by the end of March 2023, as shown in Figure \(\PageIndex{1}\) below.

Figure \(\PageIndex{1}\):  https://ourworldindata.org/excess-mortality-covid

The data from Johns Hopkins suggest that the average mortality rate was about 1% (deaths/infections).  If there were 20 million cases (based on excess deaths) out of a world population of 8 billion, the mortality rate would be nearly 0.25%. 

Another indicator of the severity of pandemics is a decrease in life expectancy.  Figure \(\PageIndex{2}\) below offers an interactive graph that shows the general rise in life expectancies since 1750, punctuated by steep drops.

Figure \(\PageIndex{2}\): Life expectancies since 1750

Note that the small drop in 2020 in the United States was caused by the COVID-19 pandemic, with some contribution from opioid-associated deaths.  The graph is dominated by a stunning decline in 1918, driven by the 1918 Flu Pandemic (historically and inaccurately known as the Spanish flu).  The large drop in life expectancy in Sweden in 1772-1773 was probably attributed to the Russian plague epidemic of 1770–1772, also known as the Plague of 1771.  Figure \(\PageIndex{3}\) below shows a history of pandemics from the Antonine Plague of 165-180 CE.  When viewing the figure, remember that the death counts are estimates at best, especially for the early pandemics.

Figure \(\PageIndex{3}\): Visualizing the History of Pandemics.  Attribution Visual Capitalist.  https://www.visualcapitalist.com/his...ics-deadliest/

The graphic omits another key plague in world history: the Plague of Athens, which struck the city from around 430 BCE to 427 BCE, during which up to 25% of the city's population died. Smallpox has emerged as a possible candidate for that outbreak.

Figure \(\PageIndex{4}\) below shows the estimated death tolls of pandemics from the Black Death of 1347-1353 through the COVID-19 pandemic.

Figure \(\PageIndex{4}\):  What were the death tolls from pandemics in history? Saloni Dattani (2023) - “” Published online at OurWorldInData.org. Retrieved from: 'https://ourworldindata.org/historical-pandemics'

The Black Death (also called the Bubonic Plague) was caused by the bacterium Yersinia pestis. Humans usually get the bubonic plague after being bitten by a rodent flea that is carrying the plague bacterium or by handling an animal infected with the plague (notice the bold letter B to help you remember Black, Bubonic, Bacterium, Bite).  The Black Death/Bubonic Plagues derives its name from the fact that many had black tissue from gangrene.  Large buboes and inflammatory swellings of lymphatic glands, especially in the groin or armpit, were common.  The pneumonic plague is a variant caused by Y. pestis.  The disease spreads when particles containing Y. pestis are inhaled into the lungs, leading to death from pneumonia and its complications. That was more infectious since it could be spread from person to person.  Modern antibiotics are used to treat the plague, which still occurs.

There have been three major known plague epidemics:

• First, the Plague of Justinian (541-750) was a bubonic plague that spread across the Mediterranean and into Europe
• The Second, or the Black Death, started in the 1340s in Central Asia, spreading into the Mediterranean and Europe in 1347, and in the next five years, it caused the death of 50% of the European population.  Following this initial death toll, the disease reoccurred regularly, becoming endemic, until the 1800s.  There were subsequent outbreaks in the late 1600s, including the Great Plagues of Seville, London, and Vienna, as well as in China.  
• Third (China), around 1855, developed from a new strain of bacteria and killed millions in China and India.  It is the form that is still occasionally found today.

Why did subsequent outbreaks of the Plague kill a lower percentage of people

One reason is that some who somehow survived the plague had some protective genes that were transmitted to future generations.  Another explanation is that the bacteria themselves became less deadly, so as not to kill off too great a percentage of their host (in this case, humans).  A key protein produced by the bacteria, critical to its virulence, is the membrane protease plasminogen activator (Pla).  It cleaves the human host precursor protein plasminogen into the active protease plasmin.  Plasmin then cleaves fibrin clots, allowing less restrictive bacterial movement to infect additional sites in the host.  Genomic analysis of Y. pestis recovered from human remains 100 years into the 1st and 2nd epidemics showed that the plasmid carrying the pPCP1 gene had a reduced copy number, contributing to lower virulence.  

This protein, Pla, is a member of a class of bacterial proteases called Omptins, which share similar sequences.  Examples include OmpT and P in E. Coli and Pla in Yersinia pestis. These transmembrane proteins form large beta-barrel structures with the active site in the extracellular domain. Substrate specificity is determined by loops emanating from the beta-barrel.  The omptins are vital in the pathogenesis of the bacterium.  In contrast to serine proteases, which have a Ser-His-Asp catalytic triad in which the serine acts as the catalytic nucleophile, omptins have two key catalytic residues, His and Asp, with a water molecule positioned in the active site acting as the catalytic nucleophile. Three active site aspartates and one histidine (D84, D86, D206, and H208) are conserved in all ompatin active sites.  

The figure below shows an interactive iCn3D model of the Yersinia Pestis Plasminogen Activator Pla (2X55).

 Figure:  Yersinia Pestis Plasminogen Activator Pla (2X55). (Copyright; author via source). Click the image for a popup or use this external link: https://www.ncbi.nlm.nih.gov/Structu...4b08c6c085ce54 

Two waters (represented by a sphere symbolizing oxygen) are included.  Water 2 (W2) is between D84 and D86 and is oriented as in aspartic (as opposed to serine) proteases.  These two asparates coordinate W2, which acts as the catalytic nucleophile.  

 

---

Measles:  A disease not shown in the figure is measles,  which has probably killed upwards of 200 million people throughout time.  It emerged from rinderpest, a viral infection that affects cattle, deer, and buffalo. In 2021, there were 128,000 deaths out of 9 million cases worldwide, even though there is a highly effective vaccine.  Vaccinations have decreased since the COVID-19 pandemic.  Since it is one of the most infectious viruses known, and one contract leads to life-long immunity, a large population (250,00-500,000) is needed to self-sustain. The most recent analysis of historical sequences suggests that it emerged (jumped to humans) around the 6th century BCE, when cities of sufficient population formed, allowing its emergence.  An RNA virus causes measles, and since RNA is much more labile than DNA, few historical traces of the measles virus are available. The oldest one is from 1911, and it was from this and newer viruses that a phylogenetic RNA tree was constructed using a molecular clock model, leading to a time of emergence in the 6th century BCE. Cities having a critical number of people to sustain an emergence existed about 300 BCE in North Africa, India, China, Europe, and the Near East. Rhazes (Persia, 10th century CE) mentioned a disease similar to measles.  Past pandemics of unclear etiology could have been due to measles, but it isn't easy to know.

Influenza: The influenza virus genome consists of 8 separate segments of ssRNA, much like the human genome, which resides on 23 different "segmented" chromosomes.  Because its genome consists of RNA, there are no traces of its past origin.  The human influenza virus arose from swine (causing swine flu) and from birds (causing avian flu).  Hippocrates wrote of a disease with similar symptoms in 412 BCE.  In 1357, an epidemic called “influenza di freddo,” or cold influence, swept Florence, Italy.  Figure \(\PageIndex{5}\) below shows the influenza RNA genome and transcribed proteins.

Figure \(\PageIndex{5}\): Influenza RNA genes and their protein products.  Ahmed Mostafa, Elsayed M. Abdelwhab, Thomas C. Mettenleiter, and Stephan Pleschka - mdpi.com/1999-4915/10/9/497/htm, CC BY 4.0, https://commons.wikimedia.org/w/inde...curid=92987475

The hemagglutinin (H) membrane protein, responsible for viral binding to host cells, and neuraminidase (N), required for newly replicated viruses to exit the cell and propagate in other cells, are especially key in understanding past and future pandemics.  There are 18 subtypes of H and 11 subtypes of N, comprising four types of viruses (A-D). A and B are the most common.  The main types circulating in 2022 were A (H3N2) and B (H1N1).  

Since the RNA genome is transcribed by an RNA polymerase that lacks proofreading, mutations occur during viral replication.  This leads to slow changes in viral protein sequence and structure, called antigen drift, and, in turn, to viruses that are less recognized by the host immune system.  This is why new influenza vaccines are formulated yearly (which requires growing the virus in eggs).  

Large-scale pandemics occur through antigen shifts.   This occurs when an animal, such as a pig, becomes infected with an avian virus, a not-unlikely occurrence given the co-farming of these animals in many places worldwide.  Newly replicated pig viruses could then contain some avian viral segments, which, when transmitted to humans, could cause lethal disease because the host lacks immunological memory to mount an immediate immune response.  Analyses show that an avian influenza virus caused the horrific 1918 flu pandemic. An ancestral virus from the late 1880s is related to the horse (equine) H7N7 and H3N8 viruses, as well as to bird, human, and swine viruses, and is likely the precursor of the 1918 flu virus.  This ancestral virus led to a global shift in avian influenza, contributing most of its RNA segments to the 1918 pandemic virus. Smaller pandemics in the last half of the 20^th century were likely caused by the rapid replacement of H3N2 and H1N1 genes, leading to increased evolutionary fitness and enhanced transmission.  We should be on guard as there is an ongoing, worldwide, highly virulent avian flu (H5N1) pandemic in wild birds and domestic poultry that has jumped to some animals, including humans who handle infected birds.

The hemagglutinin protein, homotrimer (3 identical protein subunits), MW 220,000, is the most abundant protein on the viral surface. Only three have adapted to humans in the 20th century, giving pandemic strains H1 (1918), H2 (1957), and H3 (1968). Three recent avian variants (H5, H7, and H9) can jump directly to humans but have low human-to-human transmissibility.

The viral hemagglutinin binds to glycoprotein receptors on human and other animal cells.  The receptor binding site on host cells contains a terminal sialic acid (Sia) covalently attached to a galactose. The sialic acid is usually connected through an α(2,3) or α(2,6) link to galactose on N-linked glycoproteins. The viral subtypes found in avian (and equine) influenza bind preferentially to host Sia α(2,3)Gal, which predominates in the avian GI tract, where viruses replicate. Human influenza virus binds preferentially to Sia α(2,6)Gal linkages on human cells.   The swine influenza HA binds to both Sia α(2,6)Gal and Sia α(2,3)Gal.  The structures of the Sia-Gal disaccharide are shown in Figure \(\PageIndex{6}\) below.

Sia α(2,6) Gal (Human and swine)	Sia α(2,3) Gal (Avian and Swine)
(made with Sweet, with an OH, not AcNH on sialic acid on C5)	(made with Sweet, with an OH, not AcNH on sialic acid on C5)

Figure \(\PageIndex{6}\): Structures of Sia α(2,6) Gal (human) and Sia α(2,3) Gal Gal (avian/swine)

The H5N1 avian virus is deadly but cannot be transmitted from person to person. Why? One reason is that it appears to bind deeply in the lungs and is not easily released during coughing or sneezing. Cell surface glycoproteins deeper in the respiratory tract appear to have Sia (α2,3) Gal linkages, which account for this pathology.

Small changes in the amino acids of the viral hemagglutinin (HA) could change the preference for binding between Sia α(2,6) Gal (the predominant human form) and Sia α(2,3) Gal (the predominant form in birds) on host cells and could dramatically affect both human lethality and transmission. Even though it was mostly of avian origin, the predominant 1918 hemagglutinin bound to the human Sia α(2,6) Gal. 

Figure \(\PageIndex{7}\) shows an interactive iCn3D model of an H1 1918 hemagglutinin with a human receptor (2WRG), in this case, just the Sia α(2,6) Gal disaccharide from a target N-linked glycoprotein.

Figure \(\PageIndex{7}\):  H1 1918 hemagglutinin with the human receptor - the Sia α(2,6) Gal dissachharide (2WRG). (Copyright; author via source). Click the image for a popup or use this external link: https://structure.ncbi.nlm.nih.gov/i...svY14r7wmnM1r5

The HAs in each of the 20^th-century influenza pandemics, 1918 (H1N1), 1957 (H2N2), and 1968 (H3N2), preferentially bound to the Sia α(2,6) Gal even though the 1918 viruses and presumably the other arose from avian viruses with a Sia α(2,3) Gal preference. 

Figure \(\PageIndex{8}\) shows an interactive iCn3D model of α-2,6-linked sialyl-galactosyl ligand binding to the H1 1918 hemagglutinin (2WRG).

Figure \(\PageIndex{8}\):  α-2,6-linked sialyl-galactosyl ligand binding to H1 1918 hemagglutinin (2WRG). (Copyright; author via source). Click the image for a popup or use this external link: https://structure.ncbi.nlm.nih.gov/i...yNJHQaQQebSuT9

A variant of the 1918 virus, A/South Carolina/1/18 (18H1), also circulated at the time.  It contained a single amino acid mutation, D225G, in the HA protein.  That variant switched the HA binding specificity on its target from Sia α(2,6) Gal to both Sia α(2,6) Gal and Sia α(2,3) Gal.  This change eliminated a salt bridge (ion-ion interaction) between K222 and D225 in the main variant (see the blue-dotted line in the above model). This allowed another key residue, Q226, to bind to the host receptor.    

The viral HA in the 2009 human influenza pandemic had K222 and D225, conferring specificity for Siaα (2,6)Gal.  Late in that pandemic (as occurred in the 1918 pandemic), a mutated version, D225G, that produced more severe symptoms was isolated.  It had also gained dual specificity.  Another mutant, D225E, did not, as the salt bridge was maintained and the binding to Sia α(2,6) Gal was strengthened.  Binding studies showed that the D225G mutants in the HA of 18H1 and 09H1 viruses bound with higher affinity than the wild-type HAs, likely allowing deeper binding to host glycoproteins in the lung.

The dissociation constant K_D and the on rate, k_on, and off rate, k_off, for the 09H1 and 18H1 hemagglutinins and relevant mutants were determined by surface plasmon resonance spectroscopy (see Chapter 5.2 for a review of SPR).  Table \(\PageIndex{1}\) below shows their values.

Hemagluttinin	Sia-Gal link	KD (μM)	kon (s^-1)	koff (M^-1s^-1)
09H1	α(2,6)	3.74	319	0.00119
09H1	α(2,3)	nd	nd	nd
09H1 D225G	α(2,6)	0.475	3650	0.00173
09H1 D225G	α(2,3)	2.24	1460	0.00327
18H1	α(2,6)	13.7	125	0.0017
18H1	α(2,3)	nd	nd	nd
18H1 D225G	α(2,6)	8.35	531	0.00444
18H1 D225G	α(2,3)	4.73	984	0.00466

Table \(\PageIndex{1}\):  Dissociation and rate constants for the interaction of hemagglutinins (H) from the 2009 and 1918 pandemics with Sia-Gal ligands.  Adapted from Zhang et al., J Virol. 2013 May;87(10):5949-58. doi: 10.1128/JVI.00545-13. Epub 2013 Mar 20. PMID: 23514882; PMCID: PMC3648181.

It's remarkable how a single amino acid change that can lead to no binding or strong binding can also alter a protein's specificity for its ligand and its role in human history.

Slower-acting but very lethal microbial diseases have taken a vast number of lives

Malaria: Each year, there are an estimated 300-500 million cases that result in about 2.7 million deaths.  Most deaths are children under 5 in sub-Saharan Africa.  The disease is caused mainly by the female Anopheles mosquito, which transmits Plasmodium falciparum and the less lethal Plasmodium vivax. In the 100 years of the 20^th century, between 150-300 million deaths have been attributed to malaria (2-5% of all deaths). It was brought to the New World from Africa by the slave trade of over 7 million Africans and from Portugal and Spain (the main colonial powers where malaria was endemic.  The bacteria probably moved from gorillas to humans in Africa long ago.  No effective vaccine has yet been developed to prevent this disease.

Proteins associated with the virus have been found in Egyptian samples dating back to 3200 BCE, and cyclic fevers associated with malaria were described in China in 270 BCE. In ancient Greece, Homer (750 BCE), Plato, and Hippocrates described it. It was probably first found in Rome between 0 and 100 CE. The virus persisted in Europe for 2000 years.  

Tuberculosis: This disease is caused by the Mycobacterium tuberculosis bacterium and is spread through the air. It is estimated that up to 1 billion people have died of TB throughout history. The BCG vaccine is somewhat effective against TB, but is not often administered, given the availability of antibiotics. Tuberculosis (TB) was called “phthisis” in ancient Greece and “tabes” in ancient Rome.  The modern common ancestor of these bacteria arose around 6000 years ago and is associated with disease in both the Old and New World.  Older strains were likely found in seals and sea lions.  Genetic analysis showed that the modern strain was present in Peru before Europeans arrived in the New World.  The disease in the Western Hemisphere probably originated from sea mammals crossing the ocean.

Vaccines against some of our worst infectious disease agents have saved millions of lives.  Here are some examples.

Figure \(\PageIndex{9}\):

Figure \(\PageIndex{9}\): :  https://ourworldindata.org/microbes-...ience-vaccines

Mathematical models show that from 12/20 through 12/22, COVID-19 vaccines prevented over 120 million infections, 18.5 million hospitalizations, and 3.2 million deaths in the United States alone. In the first year of the pandemic (12/20-12/21), models show that 14.4 million deaths (and 19.4 million excess deaths) were prevented worldwide. 

Epidemics that decimated Indigenous peoples in the New World

Before Columbus came to the New World, there was no typhoid, flu, smallpox, or measles there. These diseases occurred in Eurasia, where people lived in increasingly populated areas in close quarters with domesticated animals. Over time, they would have developed some immunity. Their microbes likely originated in domestic animals before jumping species to humans, much as modern flu viruses can be passed from swine to humans and, less frequently but more lethally, from birds to humans. Even with some immunity building, new pandemics were still utterly devastating.

Indigenous peoples in the New World were never exposed to these pathogens before the arrival of people from the Old World.  They used llamas primarily for work, not for food or milk.  Deaths were staggering.  It's estimated that 90% of indigenous people died, a far higher proportion than seen even with the Black Plague in Europe.  Imagine the loss of culture and civilization that would accompany a decline in central Mexico's population from 15 million to 1.5 million over the 100 years after 1519.  

Figure \(\PageIndex{10}\):  Sixteenth-century Aztec drawings of smallpox victims. https://en.wikipedia.org/wiki/Native..._and_epidemics

Social conditions after the initial collapse of the indigenous people in the Americas led to their continued decline, even though they would have gained some immunity.  An example is offered by Ostler, who describes the health consequences of the Indian Removal Act of 1830, which led to the forced relocation of Native people east of the Mississippi River into "Indian Territory" (Oklahoma and Kansas). As an example, 16,000 Cherokee were expelled and forced to live in camps with few resources, where up to 2000 died of measles, malaria, dysentery, and whooping cough. 1500 more died as they moved west.  More died in Oklahoma, leading to a death toll of 25% of the original group.

Cumulative death rates in the COVID-19 pandemic show that Indigenous peoples in the United States still have barriers to optimal health care.

 

Figure \(\PageIndex{11}\): Cumulative Deaths and Age-Adjusted Rates per 100,000 in the United States.

 

Infectious, Emerging, and Pandemic Diseases - Links to Climate Change

Our understanding of infectious diseases clearly shows that the world's great epidemics and pandemics have arisen when microbial pathogens jump from animals to humans who have not previously encountered them.  For example, HIV/AIDS arose when simian immunodeficiency viruses, to which non-human primates were adapted, jumped to humans in central Africa.  The best available data suggest that the SARS-CoV-2 virus jumped from bats to animals (raccoon dogs or other animals from Wuhan, China, live animal markets) and humans. However, some data suggest a lab leak. 

A Zoonotic disease (zoonosis, plural zoonoses) is a microbial infectious disease transmitted reversibly between animals and humans.  The major types of zoonoses are viral, bacterial, parasitic, mycotic/fungal,  rickettsial (obligate intracellular Gram-negative bacteria found in ticks, lice, fleas, mites, chiggers, and mammals), Chlamydial (bacteria that cause STDs), and Protozoal or unconventional (such as prions).  Most prevalent in the US are influenza, Salmonellosis, West Nile virus, Plague, coronaviruses, rabies, Brucellosis, and Lyme disease.  Vector-borne diseases are caused by bacteria, viruses, and parasites transmitted by vectors, such as arthropods like mosquitoes, ticks, sandflies, and blackflies. The range of arthropod vectors expands with global warming, as they are cold-blooded.

Several anthropogenic (human-caused) factors, including climate change, increase the chances of such jumps.  These factors, many of which are interrelated, include:

• movement of humans into environments where contact with disease-carrying organisms would increase transmission
• biodiversity loss, which allows species and their microbes to move into new areas
• land use change (deforestation, farming, etc) that allows the expansion of species and microbes into new areas
• global warming encourages the movement of species and their microbes to new areas where human exposure is more likely
• climate change-induced changes in plant life that allow altered distributions of animals and microbes
• climate change-derived changes in precipitation patterns affect species' adaptation and their microbes. 

Humans affect all these factors by driving climate change through land-use changes, including the expansion of agriculture, urbanization, and the rapid global movement of people, commodities, and other animals. 

How an NSAID led to the collapse of vultures in South Asia

Everything humans do can affect biodiversity, and our effects are not limited to just climate change.  Here is an example of the severe consequences of the change in the use of a simple drug, diclofenac, an inhibitor of cyclooxygenase II.  Diclofenac is an NSAID, a COX-2 inhibitor.  As such, it relieves inflammation by binding to COX-2.  Figure \(\PageIndex{x}\) shows an interactive iCn3D model of the diclofenac bound to the cyclooxygenase active site of COX-2 (1PXX). 

Figure \(\PageIndex{x}\): Diclofenac bound to the cyclooxygenase active site of COX-2 (1PXX). (Copyright; author via source). Click the image for a popup or use this external link: https://structure.ncbi.nlm.nih.gov/i...QiUsEz7z1dzWSA

The widespread use of this drug has led to about 100,000 excess deaths per year in India (an increase of 4% in mortality).  How can that be?  It all started with the widespread adoption of a generic version of the drug by farmers in India, who used it as an inexpensive anti-inflammatory and analgesic for livestock, which numbered over 500 million. Trace amounts of the drug remain in animal carcasses, which vultures normally eat.   The ingested drug caused liver failure, gout, and death in the birds.  A 90% reduction in Gyps vultures occurred in less than a decade.  But how did this lead to such an increase in human mortality?  It likely resulted from deaths due to the spread of diseases like rabies and other infectious diseases from other scavengers like dogs and rats, which ate the carcasses.  Dogs and rats are better vectors for transmitting diseases to humans.  In addition, deaths likely increased from poorer quality drinking water that was contaminated by the carcasses.  Economic costs from the vultures' demise have been estimated at $70 billion/year.  These "opportunity" costs arising from our choices (in this case, the use of diclofenac in livestock) are often disregarded by those who say we can't afford to address climate change and other effects on the planet.  It is the reverse!  We must address them.

Studies have shown that climate change has worsened 58% of human infectious diseases.  An invasive species that has expanded rapidly is the Tiger Mosquito (Aedes albopictus).  It is a vector of the chikungunya virus (the cause of Chikungunya fever) and the dengue virus (the cause of dengue fever and dengue hemorrhagic fever).  The change in its distribution in Europe in just 7 years is shown in Figure \(\PageIndex{12}\) below.

Figure \(\PageIndex{12}\):  Change in distribution of Asian tiger mosquito (Aedes albopictus) in Europe.  Left panel: Presence (red) of the Asian tiger mosquito (Aedes albopictus) in 2016.  Right panel: presence (red) in 2023.  European Environmental Agency. 

Another study used databases of mammalian viruses and their hosts to identify which viruses might be shared, a phenomenon that is much more likely when the species live in the same geographic area.  Machine learning was used to model how mammals might share viruses and shift their ranges in a warming world through 2070.  The study found that over 4,000 viruses could move among 3,000 species, greatly enhancing the likelihood of exchanging single and multiple viruses among species.  Bats (see below) are especially worrisome as they harbor many viruses capable of infecting humans. As bats move their habitats due to climate change, their chances of infecting new species that could infect humans increase.  

Twenty-five years of land-use changes in Australia led to altered bat (flying fox) behavior and a more permanent presence on agricultural land.  This has resulted in viral "spillover" (transmission of a pathogen from a non-human vertebrate to a human) driven by periodic food shortages, especially in winters following El Niño weather patterns (characterized by less rain, warmer temperatures, and greater temperature extremes).  These changes in bat behavior led to the emergence of the Hendra virus, which infected domestic horses (an intermediate host) and could be transmitted to humans. The virus does not cause disease in bats but leads to a high mortality rate in horses (75%) and humans (57% based on just four deaths). With climate and land-use change, bats persistently spent winters on agricultural lands near horses.  Spillovers occurred more frequently during low food conditions following an El Niño summer. 

The Black Death (Second Great Pandemic, 1347-1351) occurred during the Little Ice Age in Europe (1300-1850), leading to a great famine from 1315-1322.   There is a link between the pandemic and climate change, but it isn't easy to ascertain the strength of the association.  An association exists between periodic warm springs and wet summers in Central Asia (as inferred from tree-ring data) and outbreaks of the Plague in Europe about 15 years later. This suggests a continual reimportation of Yersinia pestis from Asian rodents into Europe and could explain why the Plague persisted there for so long.

The presence of plague in gerbils in Kazakhstan would increase with a warm spring and a wet summer, thereby increasing gerbil and flea populations.  This Moran effect (time correlation between two populations of a species due to a change in environment) is well known in population ecology.  When gerbil populations collapse, the flea density of the remaining gerbils increases, leading them to seek different hosts.  The spread across geographic distance would take time.  In the case of periodic import of fleas into Europe, it has been proposed that the 4000 km from west central Asia to the Black Sea took 10-12 years (around 350 km/y).

A study shows that climate change led to the European plague in 1347. Ice core samples show that a large injection (15 Tg) of sulfur occurred in 1345 (larger than that from the Mount Pinatubo eruption in 1991) and several smaller injections in the years before that (1329, 1336, and 1341).  These sulfur aerosols, likely from the tropics or low latitudes) would cool the climate.   Tree-ring data show Northern Hemisphere summer cooling in 1345–1347 CE.  Historical data from Japan and China, Germany, France, and Italy show decreased sunshine and increased cloudiness between 1345 and 1349 CE.  A famine is reported in the Mediterranean area from 1345 to 1347.  This led to the import of grain by Venice, Genoa, and Pisa from the Mongols, and along with it, rodent-associated plague.  

Pathogens from the North

Most attention has been given to pathogens moving northward from the south as warmer temperatures allow them to thrive in traditionally colder climates.  There is growing parallel concern about pathogens moving south from the Arctic as it warms.  The high northern latitudes have experienced the greatest increase in temperature as the planet warms. The Arctic is predicted to be ice-free in the summer.  

One major concern is that thawing the permafrost (comprising almost 1/4 of the northern hemisphere that is "permanently" frozen) will allow the release of CO₂ (a metabolic product of microbes in the presence of oxygen) and CH₄ (a metabolic product of Archaeal microbes in an anoxic environment) from organic molecules previously found in frozen soils.  (A similar concern is the release of "frozen" methane clathrates from a warmer ocean).  

An emerging concern is the "activation" of microbes from the permafrost that have been sequestered and dormant for 500,000 years or more.  Species like tardigrades, rotifers, and nematodes that can enter cryptobiosis in harsh conditions, such as freezing and dehydration, can reactivate.  Two species of nematodes (roundworms), dating back 46,000 years (based on radioactive dating), to the last years of the Pleistocene, were recovered and revived.  Periodic reoccurrences of anthrax have been reported from the release of Bacillus anthracis spores from permafrost thawed in the summer. In 2016, when average temperatures were significantly elevated (see Figure \(\PageIndex{13}\) below), over 2000 reindeer died (close to a 90% mortality rate), and close to 100 people were hospitalized from an anthrax outbreak in Siberia.  On June 20, 2020, a record temperature of 38 °C (100 °F) was set in the Russian town of Verkhoyansk! 

Figure \(\PageIndex{13}\): Color map showing land surface temperature anomalies from -12 °C  (-21.6 °F) (darkest red) to + 12 °C  (+21.6 °F) (darkest red) during the week of July 20-27, 1916.  https://earthobservatory.nasa.gov/im...n-extreme-year

We must also worry about emerging viruses released by the tundra's thawing.  As with SARS-CoV-2, we would have no immunity to these viruses.  Figure \(\PageIndex{14}\) below shows EM pictures of new infectious viruses isolated from seven ancient Siberian permafrost samples.

Figure \(\PageIndex{14}\): Morphological features guiding the preliminary identification of newly isolated viruses (negative staining, TEM).  Alempic, J.-M.; Lartigue, A.; Goncharov, A.E.; Grosse, G.; Strauss, J.; Tikhonov, A.N.; Fedorov, A.N.; Poirot, O.; Legendre, M.; Santini, S.; et al. An Update on Eukaryotic Viruses Revived from Ancient Permafrost. Viruses 2023, 15, 564. https://doi.org/10.3390/v15020564.  Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).

Panel (A) shows a large ovoid particle (1000 nm in length) of Pandoravirus yedoma (strain Y2) ( showing the apex ostiole (white arrowhead) and the thick tegument characteristic of the Pandoraviridae family.

Panel (B) shows a mixture of Pandoravirus mammoth (strain Yana14) oblate particles and of Megavirus mammoth (strain Yana14) icosahedral particles exhibiting a “stargate” (white starfish-like structure crowning a vertex, white arrowhead)

Panel (C) shows the elongated particle of Cedratvirus lena (strain DY0) (1500 nm in length) exhibits two apex cork-like structures (white arrowheads)

Panel (D) shows the elongated particle of Pithovirus mammoth (1800 nm in length) exhibiting a single apex cork-like structure (white arrowhead).

Panel (E) shows the large (770 nm in diameter) “hairy” icosahedral particle of Megavirus mammoth (strain Yana14), showing the “stargate” (white arrowhead) characteristic of the Megavirinae subfamily

Panel (F) shows the smaller icosahedral particle (200 nm in diameter) of Pacmanvirus lupus (strain Tums2), which is typical of astroviruses/pacmanviruses.

 

Fungal Diseases

We have concentrated solely on bacteria and viral epidemics/pandemics. However, we must also consider fungal outbreaks that affect human health and the foods that sustain us. Few medicines treat fungal infections, and no vaccines exist, so any outbreaks could be serious. Most grow optimally between 12-30 0C (54-86 0F), so they don't adapt easily to warm-blooded animals like humans. Nevertheless, global warming will increase their range and increase their thermal tolerance.  

Candida auris: This fungus was first found in 2009 in Japan as a cause of ear infection. It is now found worldwide.  

Batrachochytrium dendrobatidis (Bd): This affects amphibians and has caused a high loss in amphibian diversity on all continents.

Cryptococcus deuterogattii: This organism was typically found in more tropical/subtropical climates but is now also found in western Canada and the Pacific Northwest. It causes infections in people and animals. 

Puccinia striiformis:  This causes wheat rust, which devastates crops and is now moving into warmer areas.  

Fusarium graminearum:  This causes diseases in wheat and other food crops, especially in warm and wet conditions.

Coccidioides immitis:  This fungus, which grows in desert soil, can also spread through severe dust storms that cause fungal spores to be blown over wide regions. An example is the dispersal of Coccidioides immitis from Bakersfield, where it was endemic, to Sacramento County, where it wasn't, in 1977.  Another example is Apophysomyces trapeziformis, which caused disease in 2011 in Joplin, Missouri, after a tornado. The fungus actively thrives in wet soils but forms spores in dry conditions. These spores can last for decades and cause disease when blown into the air and inhaled.  They are associated with Valley Fever and affect farm workers who spend much time outdoors.  Latino, Asian, and Native American people get Valley Fever at 2-4 times the rate of others.

 

Bats, Viruses, and Climate Change

We have seen new infectious diseases arise from pathogen jumps from other species to humans.  The more distant the species, the more unlikely humans are to have encountered the disease, and the more likely it is to cause severe illness and pandemics. A clear example is the avian flu that led to the 1918 pandemic.  Yet we also have to worry about zoonoses from pathogen transfer from mammals, including rodents, bats, moles, shrews, monkeys, pigs, camels (a host of the deadly MERS virus), whales, cats, dogs, and seals (a likely source of the original TB virus).  

Bats are a key source of zoonotic disease, including Middle East respiratory syndrome (MERS), which has a death rate of around 35%.  Bats are the source of COVID-19, and MERS-CoV causes MERS.  The virus spreads from camels to people. Severe acute respiratory syndrome (SARS) is another coronaviral disease caused by the SARS-associated coronavirus (SARS-CoV), which emerged in China in 2003.  It had a death rate of around 12%, but it was much higher in older people. Neither of these became a full-blown pandemic, unlike the case with th3 SARS-CoV-2 virus, the cause of the COVID-19 pandemic. In addition, bat viruses include rabies, Ebola, and Marburg viruses, as well as Nipah and Hendra viruses. Bats are more likely to be infected with zoonotic viruses than rodents. 

Why are bat viruses so key in our worst zoonotic diseases?  Two features are important.  The same viruses that are so virulent to humans do not kill bats.  A clue as to the special nature of bats is that they are the only flying mammals.  What might protect bats from their viruses is that their core temperatures are quite elevated during flight, which requires a high metabolic rate.  These high temperatures likely prevent these viruses from harming bats but also make them immune to the high-temperature fevers that accompany infection in humans. The average core temperature of flying bats derived from various species was 39.6 ⁰C or 103.3 ⁰F.  Many pathogens replicate optimally at temperatures less than normal body temperature.  

Fevers in humans are regulated by the hypothalamus, mainly through prostaglandin E2 (PGE2).  This response is part of the innate immune response and is elicited by most pathogens.  PGE₂ binds to the E-prostanoid-3 receptor (EP3), a G protein-coupled receptor in the hypothalamus, which determines the "set point" for body temperature.  Hypothalamic PGE2 is produced from the endocannabinoid 2-arachidonylglycerol by the action of monoacylglycerol lipase, at least in mice stimulated with a bacterial cell wall component (LPS), which stimulates fever production.  

Figure \(\PageIndex{15}\) shows an interactive iCn3D model of the human prostaglandin E receptor EP3 bound to prostaglandin E2 (6AK3).

Figure \(\PageIndex{15}\): Human prostaglandin E receptor EP3 bound to prostaglandin E2 (6AK3).. (Copyright; author via source). Click the image for a popup or use this external link: https://structure.ncbi.nlm.nih.gov/i...cCgTGEKu3KoGx9

The model shows a dimer of two GPCRs, each bound to 1 PGE2.

Research suggests that bats have also evolved to have a lower inflammatory response mediated by the inflammasome (discussed in Chapter 5.4).  Here is a short review of the inflammasome, modified from that chapter section.  It's necessary to provide readers with a more biochemical explanation of immunosuppression in bat cells, a topic critical to understanding bats' role in present and future pandemics.  

Many pathogens or damaged host molecules activate the inflammasome, part of the innate immune system.  Our innate system immune cells (dendritic cells, macrophages, eosinophils, etc) have receptors that recognize common pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharides (LPS) on the surface of bacteria, mannose on bacteria and yeast, flagellin from bacterial flagella, dsRNA (from viruses) and nonmethylated CpG motifs in bacterial DNA. These antigens are recognized by pattern recognition receptors (PRRs) - specifically the Toll-like Receptors (TLRs) 1-10. These include plasma membrane TLRs (TL4 for LPS, TL5 for flagellin, TLRs 1, 2, and 6 for membrane and wall components of fungi and bacteria) and intracellular endosomal TLRs (TLR3 for dsRNA, TLR 7 and 8 for ssRNA and TLR9 for dsDNA).

Figure \(\PageIndex{16}\) shows the TLR family, their binding signals, and intracellular adapter proteins that transmit signals into the cell.

Figure \(\PageIndex{16}\): TLR family, their binding signals, and intracellular adapter proteins Ji-Yoon Noh, Suk Ran Yoon, Tae-Don Kim, Inpyo Choi, Haiyoung Jung, "Toll-Like Receptors in Natural Killer Cells and Their Application for Immunotherapy", Journal of Immunology Research, vol. 2020, Article ID 2045860, 9 pages, 2020. https://doi.org/10.1155/2020/2045860. This is an open-access article distributed under the Creative Commons Attribution License

 

Inflammasomes are also activated by Damage-associated molecular patterns (DAMPs).  These are typically found on molecules released from the cell or intracellular compartments upon cellular damage (hence the name DAMP). Many are nuclear or cytoplasmic proteins released from the cells. These would now find themselves in a more oxidizing environment, further changing their properties. Common DAMP proteins include heat shock proteins, histones, and high mobility group proteins (both nuclear and cytoskeletal). Some other common non-protein DAMPS can be released in response to cellular damage: ATP, uric acid, heparin sulfate, DNA, and cholesterol crystals. In the wrong location, these can be considered danger signals.  They are sometimes referred to as "sterile" signals.

If TLRs recognize PAMPs, what recognizes DAMPs? They are recognized by another type of intracellular pattern recognition receptor (PRR) called NOD (Nucleotide-binding Oligomerization Domain (NOD)- Like Receptors or NLRs). NLRs also recognize PAMPs. The abbreviation NLR also comes from the Nucleotide-binding domain (NBD) and Leucine-Rich repeat (LRR)–containing proteins (NLR)s. This family of proteins participates in the formation of a large protein structure called the inflammasome. (Sorry about the multiple abbreviations and naming systems!)

As both PAMPs and DAMPs pose dangers, it would make sense that, once they recognize their cognate PRRs (TLRs and NLRs, respectively), pathways emanating from the occupied receptors might converge in a common effector system that releases inflammatory cytokines from immune cells. Since uncontrolled immune effector release during an inflammatory response can be dangerous, requiring two signals to trigger cytokine release from the cell can sometimes be helpful. 

Two such inflammatory cytokines are Interleukin 1-β (IL 1-β) and IL-18. Activation of TLRs by a PAMP activates a potent transcription factor, NF-κB, which then transcriptionally activates the gene for the precursor of the cytokine, pro-interleukin-1β. Without a specific proteolytic cleavage, the active cytokine will not be released from the cell.

A signal arising when a DAMP activates an NLR activates the protease required for this cleavage. This leads to the proteolytic activation of another inactive protease, procaspase 1, on the inflammasome. The activated inflammasome then activates procaspase, producing caspase (a cysteine-aspartic protease).

The convergence of the signals from the PAMP activation of a TLR and DAMP activation of a NLR at the inflammasome is shown in Figure \(\PageIndex{17}\).

Figure \(\PageIndex{17}\): Signals from PAMP activation of a TLR and DAMP activation of an NLR at the inflammasome

The active cytokine interleukin 1-β helps recruit innate immune cells to the site of infection. It also affects the activity of immune cells in the adaptive immune response (T and B cells). Active IL-18 increases another cytokine, interferon-gamma, and enhances the activity of T cells that kill other cells.

Figure \(\PageIndex{18}\) shows an interactive iCn3D model of the NLRP3 double-ring cage, 6-fold (12-mer) (7LFH)

Figure \(\PageIndex{18}\): NLRP3 double-ring cage, 6-fold (12-mer) (7LFH). (Copyright; author via source). Click the image for a popup or use this external link: https://structure.ncbi.nlm.nih.gov/icn3d/share.html?DEbdkUoBtqRQ9bu59

 

The full-length mouse NLRP3 forms a 12 to 16-mer organized in a double-ring cage. It is held together by interactions between the leucine-rich repeats (LRR) domains. The structure shields the pyrin domains, so they will not be activated without appropriate signals. The complex is also localized to the membrane. NLRP3 inflammasomes appear to be activated by cellular stress and exposure to pathogens. It is one of the main responders to a variety of microbial infections. 

In summary, two signals are again needed:

Signal 1

The first signals are the bacterial and viral PAMPs (influenza virus, poliovirus, enterovirus, rhinovirus, human respiratory syncytial virus, etc.), which bind to TLRs and activate the NFkB transcription factor. This activates not only the transcription of pro-interleukin 1-β and interleukin 18 but also the transcription of the NLRP3 sensor itself.

Signal 2

Signal 2 is delivered to the sensor NLRP3 indirectly via PAMPs and DAMPs.  This leads to the assembly of the inflammasome. These DAMPs prime the activation of the NLRP3 protein and subsequent formation of the active NLRP3 inflammasome. But what activates NLR3P3? After many studies, it became clear that the typical bacterial ligands that would activate TLRs and perhaps NLRs only prime NLRP3 for activation. They don't bind to it directly.

Extracellular ATP is a major activator of NLRP3. Nanoparticles are also known to release ATP. Most studies show that K⁺ efflux from the cell is an early signal.   

Back to Bats

To survive the viruses they harbor, bats decrease their inflammatory response upstream at the level of PAMP and DAMP recognition and downstream at the level of caspase-1 inhibition. In addition, cleavage sites in IL-1β lead to its proteolytic degradation. These events decrease inflammasome signaling. That multiple steps are inhibited suggests that evolutionary pressures have selected them.

The activation of the bat NLRP3 inflammasome by a "sterile" agent (ATP) and 3 RNA viruses is significantly decreased in bat cells compared to responses to these signals in humans and in mice cells. The viruses include:

• H1N1 influenza A virus (a negative-sense single-stranded RNA virus known to activate the NLRP3 inflammasome);
• the Melaka virus (a bat-borne zoonotic double-stranded RNA virus);
• MERS-CoV (a positive-sense (+) ssRNA zoonotic virus).

Even though the secretion of interleukin-1β is inhibited in bat cells, viral loads remained high in virally infected bat cells. The altered NLRP3 activation in bat cells occurs partly through decreasing RNA splicing and an altered LRR domain in NLRP3.  

It should be clear that if the bat population increases or moves to new habitats (both events could be promoted by climate change), humans are at greater risk of bat-derived pandemics.  Coronaviruses, with over 3000 species, comprise about 1/3 of the bat's viral load.  The region comprising southern Yunnan (in China, Myanmar, and Laos) has very high bat populations, and it is from these areas that new bat zoonoses are likely to emerge.  Comparing models of past climate (in the 1900s) and bat species richness with present climatic conditions, along with knowledge of the specific climate conditions necessary to support bat populations and diversity, shows that the greatest increase in bat species populations in the 20th century occurred in Southeast Asia.  Less important sites included regions in Central Africa and some pockets of Central and South America.  The region in China, Myanmar, and Laos is likely the origin of the SARS-CoV-1 and SARS-CoV-2 viruses.  

Summary

This chapter establishes how the world's major pandemic diseases arise, documents their historical devastation, and develops the molecular, ecological, and climatological connections between climate change and emerging infectious disease risk.

Historical pandemics and their molecular bases. Major pandemics arise when pathogens jump from animal reservoirs to immunologically naive human populations. The Black Death (Yersinia pestis, three major epidemics from 541 CE to the present) killed 50% of Europe's population in five years during the second pandemic. The key virulence factor is Pla, a membrane-spanning beta-barrel omptin protease that cleaves plasminogen to plasmin, dissolving fibrin clots to facilitate bacterial dissemination; its catalytic mechanism employs a His/Asp dyad with water as the nucleophile (distinct from serine proteases). Reduced copy number of the pPCP1 plasmid encoding Pla contributed to the lower lethality of later plague epidemics alongside host genetic selection and bacterial attenuation. Measles — which has likely killed over 200 million people — emerged from rinderpest around the 6th century BCE when cities reached the 250,000–500,000 population threshold needed to sustain the virus, demonstrated by molecular clock phylogenetics of RNA sequences. Malaria (300–500 million cases annually, 2.7 million deaths, mostly children under 5 in sub-Saharan Africa) and tuberculosis (estimated 1 billion deaths throughout history) represent slower-acting but persistently devastating pathogens. Vaccines have been transformative: COVID-19 vaccines alone prevented over 3.2 million US deaths and 14.4 million global deaths in their first year.

Influenza: molecular determinants of pandemic potential. Influenza's 8-segment ssRNA genome, replicated by an error-prone polymerase, enables two modes of evolutionary change. Antigenic drift — gradual accumulation of mutations in hemagglutinin (HA) and neuraminidase (N) — drives the need for annual vaccine reformulation. Antigenic shift — reassortment of entire RNA segments when two strains co-infect a single cell (as in swine) — generates novel pandemic strains to which humans have no prior immunity. The 1918 H1N1 pandemic, the deadliest in recorded history, arose from an avian precursor. Host specificity is determined biochemically by HA binding preference: avian strains bind Sia α(2,3)Gal (predominant in avian GI tract and deep human lung), while human strains bind Sia α(2,6)Gal (predominant on human upper respiratory epithelium). The 1918 HA acquired human-type Sia α(2,6)Gal specificity despite avian origin. A single substitution, D225G, disrupts the K222–D225 salt bridge in HA, permits Q226 receptor contact, and shifts binding to dual Sia α(2,6)Gal/Sia α(2,3)Gal specificity with dramatically increased affinity (KD drops from 13.7 to 4.73 μM for 18H1). This dual specificity, which emerged late in both the 1918 and 2009 pandemics, enables deeper lung binding and greater severity. The ongoing H5N1 avian influenza pandemic in wild birds and poultry — which currently lacks efficient human-to-human transmission due to its Sia α(2,3)Gal preference and deep lung binding — represents an urgent surveillance priority.

Climate change and the amplification of zoonotic disease risk. Zoonotic diseases — transmitted reversibly between animals and humans — are the source of most emerging pandemic threats. Six interconnected anthropogenic factors amplify spillover risk: human encroachment into wildlife habitats; biodiversity loss releasing niches for disease-carrying species; land-use change through deforestation and agriculture; climate-driven range shifts of vectors, hosts, and pathogens; altered plant distributions affecting animal habitat; and changed precipitation patterns affecting host-pathogen ecology. The diclofenac/vulture case study illustrates cascading biodiversity collapse: COX-2 inhibition in livestock → vulture mortality (90% reduction in a decade) → replacement by rat and dog scavengers → increased rabies and infectious disease transmission → ~100,000 excess human deaths per year in India and estimated $70 billion annual economic cost. Machine learning models project that >4,000 viruses could move among ~3,000 mammalian species by 2070 as climate shifts overlap species ranges. The tiger mosquito (Aedes albopictus), a vector for chikungunya and dengue, dramatically expanded its European range between 2016 and 2023.

Permafrost pathogens and fungal diseases. Arctic warming poses a dual threat: thawing permafrost releases CO₂ and CH₄ (climate feedback) and reactivates dormant pathogens dormant for up to 500,000 years. Anthrax spores (Bacillus anthracis) released from permafrost killed over 2,000 reindeer and hospitalized nearly 100 people in Siberia in 2016 during record temperature anomalies. Novel giant viruses isolated from ancient Siberian permafrost samples — including Pandoravirus, Megavirus, Cedratvirus, Pithovirus, and Pacmanvirus species — represent potential threats against which modern humans have no immunity. Fungal pathogens represent an underappreciated but growing threat: Candida auris has become a global nosocomial pathogen since 2009; Cryptococcus deuterogattii has expanded from tropical to temperate regions; Coccidioides immitis causes Valley Fever through dust-dispersed spores with disproportionate impact on Latino, Asian, and Native American agricultural workers; and wheat rust (Puccinia striiformis) threatens food security. No vaccines exist for fungal diseases and treatment options are limited.

Bats as pandemic reservoirs: the inflammasome connection. Bats are uniquely important viral reservoirs — harboring SARS-CoV-1, SARS-CoV-2, MERS-CoV, Ebola, Marburg, Nipah, Hendra, and rabies viruses without succumbing to them. Two mechanisms explain bat viral tolerance: elevated core temperatures during flight (~39.6°C, equivalent to a persistent high fever) that suppress viral replication, making bats effectively fever-resistant; and evolutionarily selected suppression of NLRP3 inflammasome signaling at multiple levels. The NLRP3 inflammasome normally requires two signals for activation: Signal 1 (PAMPs binding TLRs activate NF-κB, inducing pro-IL-1β and NLRP3 transcription) and Signal 2 (DAMPs and PAMPs activate NLR/NLRP3 assembly, recruiting procaspase-1 for cleavage into active caspase-1, which then processes pro-IL-1β and pro-IL-18 into active inflammatory cytokines). Bats suppress this cascade at multiple nodes — reduced PAMP/DAMP recognition, decreased NLRP3 RNA splicing, altered LRR domain structure, caspase-1 inhibition, and IL-1β proteolytic degradation — maintaining high viral loads without lethal inflammatory pathology. In humans, the same viruses trigger uncontrolled NLRP3 activation and cytokine storm. Climate-driven habitat shifts of bat populations — especially in the Southeast Asian region of southern Yunnan, Myanmar, and Laos (the likely source of both SARS-CoV-1 and SARS-CoV-2) — increase the probability of spillover into new mammalian hosts and ultimately humans, making this one of the most urgent climate-health connections requiring international scientific surveillance and preparedness.

 

---