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The COVID-19 pandemic is extraordinary, but many ordinary events have contributed to its becoming and persistence. Here, we argue that the emergence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, which has radically altered day-to-day life for people across the globe, was an inevitability of contemporary human ecology, presaged by spillovers past. We show the ways in which the emergence of this virus reiterates other infectious disease crises, from its origin via habitat encroachment and animal use by humans to its evolution of troublesome features, and we spotlight a long-running crisis of inequitable infectious disease incidence and death. We conclude by describing aspects of SARS-CoV-2 and the COVID-19 pandemic that present opportunities for disease control: spaces for intervention in infection and recovery that reduce transmission and impact. There are no more “before times”; therefore, we encourage embracing a future using old mitigation tactics and government support for ongoing disease control.

International audience; Infectious diseases are among the strongest selective pressures driving human evolution1,2. This includes the single greatest mortality event in recorded history, the first outbreak of the second pandemic of plague, commonly called the Black Death, which was caused by the bacterium Yersinia pestis3. This pandemic devastated Afro-Eurasia, killing up to 30-50% of the population4. To identify loci that may have been under selection during the Black Death, we characterized genetic variation around immune-related genes from 206 ancient DNA extracts, stemming from two different European populations before, during and after the Black Death. Immune loci are strongly enriched for highly differentiated sites relative to a set of non-immune loci, suggesting positive selection. We identify 245 variants that are highly differentiated within the London dataset, four of which were replicated in an independent cohort from Denmark, and represent the strongest candidates for positive selection. The selected allele for one of these variants, rs2549794, is associated with the production of a full-length (versus truncated) ERAP2 transcript, variation in cytokine response to Y. pestis and increased ability to control intracellular Y. pestis in macrophages. Finally, we show that protective variants overlap with alleles that are today associated with increased susceptibility to autoimmune diseases, providing empirical evidence for the role played by past pandemics in shaping present-day susceptibility to disease.

Bartonet al.1raise several statistical concerns regarding our original analyses2that highlight the challenge of inferring natural selection using ancient genomic data. We show here that these concerns have limited impact on our original conclusions. Specifically, we recover the same signature of enrichment for high FSTvalues at the immune loci relative to putatively neutral sites after switching the allele frequency estimation method to a maximum likelihood approach, filtering to only consider known human variants, and down-sampling our data to the same mean coverage across sites. Furthermore, using permutations, we show that the rs2549794 variant nearERAP2continues to emerge as the strongest candidate for selection (p = 1.2×10−5), falling below the Bonferroni-corrected significance threshold recommended by Bartonet al. Importantly, the evidence for selection onERAP2is further supported by functional data demonstrating the impact of theERAP2genotype on the immune response toY. pestisand by epidemiological data from an independent group showing that the putatively selected allele during the Black Death protects against severe respiratory infection in contemporary populations.

The local slaughterhouse’s coronavirus cluster was the first large outbreak we heard about in Champaign County. The sprawling pork processing plant sits in the midst of cornfields some 17 miles north of the University of Illinois at Urbana-Champaign. Until early May, workers there processed 35 million pounds of pork a month. The company reported its first case on 25 April. Health inspectors arrived two days later to find the plant 90 percent out of compliance in its infection control practices. By 15 May, after testing 200 of the 627 workers for COVID-19, 83 got positive results. Management admitted it was ‘complex’ to track employees being tested and to follow up with those who had to be quarantined. That’s when they contacted the University of Illinois at Urbana-Champaign. They then announced confidently to the local press: We’ve got it under control. We have the scientists now.

Many genes that respond to infection have functions outside of immunity and have been found to be under natural selection. Pathogens may therefore incidentally alter nonimmune physiology through engagement with immune system genes. This raises a logical question of how genetically promiscuous the immune system is, here defined as how heavily cross-referenced the immune system is into other physiological systems. This work examined immune gene promiscuity across physiological systems in primates by assessing the baseline (unperturbed) expression of key tissue and cell types for differences, and primate genomes for signatures of selection. These efforts revealed "immune" gene expression to be cross-referenced extensively in other physiological systems in primates. When immune and nonimmune tissues diverge in expression, the differentially expressed genes at baseline are enriched for cell biological activities not immediately identifiable as immune function based. Individual comparisons of immune and nonimmune tissues in primates revealed low divergence in gene expression between tissues, with the exception of whole blood. Immune gene promiscuity increases over evolutionary time, with hominoids exhibiting the most cross-referencing of such genes among primates. An assessment of genetic sequences also found positive selection in the coding regions of differentially expressed genes between tissues functionally associated with immunity. This suggests that, with increasing promiscuity, divergent gene expression between the immune system and other physiological systems tends to be adaptive and enriched for immune functions in hominoids.

Despite the effectiveness of face masks in reducing the spread of COVID-19, many people refused to wear them. Previous studies have shown how a variety of demographic and individual difference factors (e.g., political orientation, stress, perceived risk of infection) predict use of masks. However, people’s health protective behavior can vary depending on the context they are in – a fact that has been thus far neglected in the mask wearing literature. Here, we surveyed an international sample of participants (N = 634, August, 2020) about their use of masks while engaging in routine and leisure activities during the first six months of the COVID-19 pandemic. People were more likely to use masks during routine than during leisure activities. In addition, wearing masks during routine activities was positively associated with pandemic-related stress, the intention to protect oneself and others, and feeling safe when others wear masks in public. Wearing masks during leisure activities was only positively associated with the intention to protect oneself and the belief that wearing masks is the right thing to do. Results also suggest that political orientation and future time orientation may have different effects on mask wearing in routine activities vs. leisure activities, warranting further study. Understanding the person by situation interactions that predict protective behaviors might help us combat future airborne transmissible diseases.

Despite their close genetic relatedness, apes and African and Asian monkeys (AAMs) differ in their susceptibility to severe bacterial and viral infections that are important causes of human disease. Such differences between humans and other primates are thought to be a result, at least in part, of interspecies differences in immune response to infection. However, because of the lack of comparative functional data across species, it remains unclear in what ways the immune systems of humans and other primates differ. Here, we report the whole-genome transcriptomic responses of ape species (human and chimpanzee) and AAMs (rhesus macaque and baboon) to bacterial and viral stimulation. We find stark differences in the responsiveness of these groups, with apes mounting a markedly stronger early transcriptional response to both viral and bacterial stimulation, altering the transcription of ~40% more genes than AAMs. Additionally, we find that genes involved in the regulation of inflammatory and interferon responses show the most divergent early transcriptional responses across primates and that this divergence is attenuated over time. Finally, we find that relative to AAMs, apes engage a much less specific immune response to different classes of pathogens during the early hours of infection, up-regulating genes typical of anti-viral and anti-bacterial responses regardless of the nature of the stimulus. Overall, these findings suggest apes exhibit increased sensitivity to bacterial and viral immune stimulation, activating a broader array of defense molecules that may be beneficial for early pathogen killing at the potential cost of increased energy expenditure and tissue damage. Copyright

Objective. Since the COVID-19 pandemic began, wearing protective facial masks has become a divisive issue. Yet little is known about what drives individual differences in mask wearing. Methods and Measures. Here we surveyed an international cohort of participants (N = 753), about their use of masks and other variables related to mask wearing over three periods from July-August, 2020. Results. We found that greater prevalence of COVID-19, higher perceived risk of infection, stress, and future orientation predicted more frequent use of masks. Future-oriented people also experienced greater stress and reported higher perceived risk of infection. Conclusion. Results indicate that perceived risk of infection, stress, and future orientation reliably accounted for variation in reported mask-wearing behavior, but individual differences in mask-wearing intentions (e.g., protect self vs. others), and intergroup relations (e.g., political affiliation) should be considered in future investigations.

Despite their close genetic relatedness, apes and African and Asian monkeys (AAMs), strongly differ in their susceptibility to severe bacterial and viral infections that are important causes of human disease. Such differences between humans and other primates are thought to be a result, at least in part, of inter-species differences in immune response to infection. However, due to the lack of comparative functional data across species, it remains unclear in what ways the immune systems of humans and other primates differ. Here, we report the whole genome transcriptomic responses of ape species (human, common chimpanzee) and AAMs (rhesus macaque and olive baboon) to bacterial and viral stimulation. We find stark differences in the responsiveness of these groups, with apes mounting a markedly stronger early transcriptional response to both viral and bacterial stimulation, altering the transcription of ∼40% more genes than AAMs. Additionally, we find that genes involved in the regulation of inflammatory and interferon responses show the most divergent early transcriptional responses across primates and that this divergence is attenuated over time. Finally, we find that relative to AAMs, apes engage a much less specific immune response to different classes of pathogens during the early hours of infection, upregulating genes typical of anti-viral and anti-bacterial responses regardless of the nature of the stimulus. Overall, these findings suggest apes exhibit increased sensitivity to bacterial and viral immune stimulation, activating a broader array of defense molecules that may be beneficial for early pathogen killing at the potential cost of increased energy expenditure and tissue damage.

Among mammals, humans are exquisitely sensitive to lipopolysaccharide (LPS), an environmentally pervasive bacterial cell membrane component. Very small doses of LPS trigger powerful immune responses in humans and can even initiate symptoms of sepsis. Close evolutionary relatives such as African and Asian monkeys require doses that are an order of magnitude higher to do the same. Why humans have evolved such an energetically expensive antimicrobial strategy is a question that biological anthropologists are positioned to help address. Here we compare LPS sensitivity in primate/mammalian models and propose that human high sensitivity to LPS is adaptive, linked to multiple immune tactics against pathogens, and part of multi-faceted anti-microbial strategy that strongly overlaps with that of other mammals. We support a notion that LPS sensitivity in humans has been driven by microorganisms that constitutively live on us, and has been informed by human behavioral changes over our species' evolution (e.g., meat eating, agricultural practices, and smoking).

Status alters immune function in macaques Rhesus macaques experience variable levels of stress on the basis of their position in the social hierarchy. To examine how stress affects immune function, Snyder-Mackler et al. manipulated the social status of individual macaques (see the Perspective by Sapolsky). Social status influenced the immune system at multiple levels, from immune cell numbers to gene expression, and altered signaling pathways in a model of response to infection. Macaques possess a plastic and adaptive immune response wherein social subordination promotes antibacterial responses, whereas high social status promotes antiviral responses. Science , this issue p. 1041 ; see also p. 967

Here, we present a mechanistically grounded theory detailing a novel function of the behavioral immune system (BIS), the psychological system that prompts pathogen avoidance behaviors. We propose that BIS activity allows the body to downregulate basal inflammation, preventing resultant oxidative damage to DNA and promoting longevity. Study 1 investigated the relationship between a trait measure of pathogen avoidance motivation and in vitro and in vivo proinflammatory cytokine production. Study 2 examined the relationship between this same predictor and DNA damage often associated with prolonged inflammation. Results revealed that greater trait pathogen avoidance motivation predicts a) lower levels of spontaneous (but not stimulated) proinflammatory cytokine release by peripheral blood mononuclear cells (PBMCs), b) lower plasma levels of the proinflammatory cytokine interleukin-6 (IL-6), and c) lower levels of oxidative DNA damage. Thus, the BIS may promote health by protecting the body from the deleterious effects of inflammation and oxidative stress.

The human immune system is under great pathogen-mediated selective pressure. Divergent infectious disease pathogenesis across human populations combined with the overrepresentation of "immune genes" in genomic regions with signatures of positive selection suggests that pathogens have significantly altered the human genome. However, important features of the human immune system can confound searches for and interpretations of signatures of pathogen-mediated evolution. Immune system redundancy, immune gene pleiotropy, host ability to acquire immunity and alter the immune repertoire of offspring through "priming," and host microbiome complicate evolutionary interpretations of host-pathogen interactions. The overall promiscuity and sensitivity of the immune system to local environments can also muddy assumptions about the origins of a selective pressure on a given set of genes. This review addresses (a) how features of the immune system, the primary buffer between a pathogen and the human genome, affect evolutionary signal and (b) the considerations that must be made when assessing how pathogens have contributed to human diversification.

Humans and apes are neutrophilic, maintaining high levels (50–70% of circulating leukocytes) of this short-lived, highly reactive cell type (neutrophils), while most primates maintain significantly lower proportions(20–40% circulating leukocytes). Neutrophils are key limiters of bacterial and parasitic infection, amplifying inflammation, phagocytosing and presenting, and trapping invading foreign material, as well as committing bystander tissue damage in these efforts. The comparative neutrophilia of humans, therefore, suggests alterations in neutrophil activities such that higher proportions are both required and tolerated in this species. To address this possibility, we analyzed transcriptomic, and cell physiological responses of neutrophils from humans, and two biomedically important primates, rhesus macaque and common marmoset. Cells were isolated via a density gradient and stimulated with 1ng-1ug of lipopolysaccarhide (LPS) from Escherichia coli K12 or the bacteria itself (MOI 10:1) for 1–3 hours. Transcriptomic responses were captured by RNAseq, and physiological responses [phagocytosis, apoptosis, extracellular trapping (NETing)] by fluorescent microscopy. The species differed strongly the expression of genes in innate immune and cell trafficking pathways. Overall, primates exhibited NETing and apoptosis sensitivity to even the lowest dose of LPS. Humans, however, displayed a unique complement of neutrophil antimicrobial responses - phagocytosing and apoptosising more, while NETing less than the other species. These results suggest inter-species differences in important neutrophil antimicrobial strategies that may impact interpretation of primate biomedical models.

As African catarrhines, the common chimpanzee (Pan troglodytes) and baboon (Papio sp.) share 98.6% and 94% of their genomes, respectively, with humans and are considered important models of human infectious disease [4, 6, 20]. However, these species exhibit very different susceptibility to infectious bacterial pathogens that are associated, in humans, with marked dysregulation of early inflammatory responses [5, 7, 10, 12, 25]. For example, humans and chimpanzees require only small doses (i.e. 2-5 ng/kg) of Gram-negative bacteria or cell wall component lipopolysaccharide (LPS) to initiate severe bacterial sepsis, while baboons and other old world monkey species require much higher doses (0.1 mg/kg) [7, 18, 22, 24]. Similarly, humans and chimpanzees are very susceptible to Neisseria gonorrhea infections, while baboons and most other mammals are resistant [12]. Though less well understood, mycobacterial infections have been noted to rapidly progress in baboons and other old world monkeys [9, 16, 26]. The host factors responsible for disparate bacterial infection susceptibility in catarrhine primates [humans, apes, and old world monkeys (i.e. baboons, macaques)] are not well understood, though blood leukocyte reactivity to immune stimuli during early infection appears to differ between such species [2, 19, 24]. One possible explanation for disparate bacterial infection susceptibility between human, chimpanzees and baboons is inter-species differences in the initiation of the early innate immune responses. The first two hours of infection in mammalian hosts is marked by an immediate induction of a core set of innate immune genes (i.e. cytokines and chemokines) that appear to exert control over the initial infection course and may affect disease susceptibility [8, 15]. Toll-like receptors (TLRs) are innate immune system receptors that assist in initiating this highly organized early innate immune response by recognizing pathogen-associated molecular patterns (PAMPs) and triggering immune gene induction. TLR2 recognizes lipoproteins and lipopeptides from Gram-positive bacteria, mycobacteria, fungi and parasites while TLR4 interacts with lipopolysaccharide LPS from Gram-negative bacteria [3, 13, 21]. Given the importance of chimpanzee and baboon models in understanding human disease course, comparative data on early TLR-mediated responses to bacterial PAMPs may contribute to a better understanding of the host factors responsible for inter-species differences in bacterial disease susceptibility. This study compares and contrasts the induction profile of chemokines and cytokines associated with the early innate immune response in humans, chimpanzees and baboons after stimulation with TLR2 and 4-detected PAMPs. To investigate catarrhine early innate immune responses to TLR-detected bacterial PAMPs fresh blood from unrelated, healthy, adult humans (City College of New York IRB # 09-0073C), chimpanzees (Yerkes National Primate Research Center, Atlanta, Georgia) and baboons (Texas Biomedical Research Institute, San Antonio, Texas) was stimulated at 37°C for 90 minutes with ten fold serial dilutions of 10 ug/ml – 0.01 ug/ml of TLR2 and TLR4-detected PAMPs [Pam3CSK4, lipomannan from Mycobacterium smegmatis (LMMS), Ultrapure lipopolysaccharide from Escherichia coli 0111:B4 (LPS), Invivogen, San Diego, CA]. Chimpanzee and baboon blood samples were humanely collected in accordance with individual institutional IACUC requirements. After 90 minutes, red blood cells were lysed by hypotonic shock and total blood leukocyte total RNA isolated to synthesize cDNA (Qiagen RNEasy mini-kit, Quantitect Reverse Transcriptase kit, Qiagen San Diego, CA). Real-time pcr was performed using 0.1 uM of primers corresponding to conserved regions of cytokine/chemokine genes of all three species (Table 1). Reaction specificity was confirmed by DNA sequencing of the amplicons. Relative gene induction was calculated using the Pfaffl equation corrected for primer efficiency, and three reference genes (GAPDH, ACTB, B2M) [17] [23]. Table 1 Genes, primer sequences and annealing sites Of 14 genes tested by this method eight showed at least two-fold induction and notable differences between species, even though there were no obvious differences in the proportions of neutrophils, lymphocytes, monocytes and basophils/eosinophils between the species (Wright-Giemsa method, data not shown). The most striking differences were among the three chemokines CXCL2, IL-8/CXCL8 and CCL3. Whereas baboons expressed high levels of CXCL2 and low levels of IL-8/CXCL8 and CCL3, this pattern was reversed for humans and chimpanzees where most humans and all chimpanzees expressed significantly higher levels of IL-8/CXCL8 and CCL3 than CXCL2 (A panels). This pattern of chemokine induction was observed for all three PAMPs and was seen even at low doses of PAMP (0.01 ug/ml, data not shown). Though a subset of chemokines, species-specific induction of these cellular chemoattractants suggests that baboon and hominoid cellular responses to bacterial infection may differ, as CXCL2 and IL-8 attract mainly neutrophils and CCL3 is a chemoattractant for a broader range of cell subtypes. A comparison of the pro-inflammatory cytokine responses, IL-1β, TNFα and IL-6, revealed that humans expressed appreciably lower levels of IL-1β and TNFα than did chimpanzees and baboons with the exception of the TNFα response to LPS which was similar for all three species (B panels). The IL-6 response, which was strikingly high for all three species, tended to be lower for baboons than for humans and chimpanzees, especially in response to LPS. These relationships were observed even at low doses of PAMPs (0.01 ug/ml, data not shown). An analysis of the anti-inflammatory cytokine responses, IL-10 and IL-1RN, also revealed striking differences between the three species. Baboons expressed very liitle IL-1RN compared to humans and chimpanzees, irrespective of the PAMPs employed (C panels). In contrast, the IL-10 response was similar for all three species with the baboon response being somewhat greater than the responses of humans and chimpanzees. Again, these relationships were conserved even at low doses of PAMPs (data not shown). In summary, this study suggests that the early innate immune responses of humans, chimpanzees, and baboons to TLR2 and TLR4-detected PAMPs differ, with the patterns, in general, being species-specific rather than agonist-specific. These species differences in cytokine/chemokine induction may affect immune cell activation and trafficking. Interestingly, the disparate baboon and hominoid cytokine/chemokine responses noted here agree with observations that cercopithecoid (old world monkey) and hominoid diverge in susceptibility to bacterial infections. It is interesting, for example, that baboon IL-8/CXCL8 and IL-6 induction tends to be minimal, as high levels of these proteins during early severe sepsis have been correlated with negative clinical outcomes [11, 14]. These studies are an early step in improving our understanding of African catarrhine innate immune responses to bacteria. As these non-human primates are important biomedical models for human medicine, it is very important to highlight inter-species differences in early innate immune function. The results of this study may help to explain inter-species differences in susceptibility to major human bacterial-mediated diseases.

The contribution of pre-mRNA processing mechanisms to the regulation of immune responses remains poorly studied despite emerging examples of their role as regulators of immune defenses. We sought to investigate the role of mRNA processing in the cellular responses of human macrophages to live bacterial infections. Here, we used mRNA sequencing to quantify gene expression and isoform abundances in primary macrophages from 60 individuals, before and after infection with Listeria monocytogenes and Salmonella typhimurium. In response to both bacteria we identified thousands of genes that significantly change isoform usage in response to infection, characterized by an overall increase in isoform diversity after infection. In response to both bacteria, we found global shifts towards (i) the inclusion of cassette exons and (ii) shorter 3’ UTRs, with near-universal shifts towards usage of more upstream polyadenylation sites. Using complementary data collected in non-human primates, we show that these features are evolutionarily conserved among primates. Following infection, we identify candidate RNA processing factors whose expression is associated with individual-specific variation in isoform abundance. Finally, by profiling microRNA levels, we show that 3’ UTRs with reduced abundance after infection are significantly enriched for target sites for particular miRNAs. These results suggest that the pervasive usage of shorter 3’ UTRs is a mechanism for particular genes to evade repression by immune-activated miRNAs. Collectively, our results suggest that dynamic changes in RNA processing may play key roles in the regulation of innate immune responses., Author Summary Changes in gene regulation have long been known to play important roles in both innate and adaptive immune responses. While transcriptional responses to infection have been well-characterized, much less is known about the extent to which co-transcriptional mechanisms of mRNA processing are involved in the regulation of immune defenses. In this study, we sought to investigate the role of mRNA processing in the cellular responses of human macrophages to live bacterial infection. Using primary human macrophages derived from whole blood samples from 60 individuals, we sequenced mRNA both before and after infection with two live bacteria. We show that immune responses to infection are accompanied by pervasive changes in mRNA isoform usage, with systematic shifts towards increased cassette exon inclusion and shortening of Tandem 3’ UTRs post-infection. These patterns are conserved in nonhuman primates, supporting their functional importance across evolutionary time. Complementary microRNA profiling revealed that shortened 3’ UTRs are enriched for target sites of macrophage-expressed miRNAs, many of which are specifically activated after infection to regulate the innate immune response. Our results therefore provide the first genome-wide empirical support for the idea that actively regulated shifts towards shorter 3’ UTRs might allow specific genes to evade repression by immune-activated miRNAs.

That many women leave science somewhere between undergraduate studies and senior scientist positions has been well noted. Honest discussion of the challenges women face within and outside the STEM ...

Chronic inflammatory and autoimmune diseases have been the focus of many genome-wide association studies (GWAS) because they represent a significant cause of illness and morbidity, and many are heritable. Almost a decade of GWAS studies suggests that the pathological inflammation associated with these diseases is controlled by a limited number of networked immune system genes. Chronic inflammatory and autoimmune diseases are enigmatic from an evolutionary perspective because they exert a negative affect on reproductive fitness. The persistence of these conditions may be partially explained by the important roles the implicated immune genes play in pathogen defense and other functions thought to be under strong natural selection in humans. The evolutionary reasons for chronic inflammatory and autoimmune disease persistence and uneven distribution across populations are the focus of this review.

The primate immune system is the outcome of hundreds of millions of years of complex evolution. Its divergence from the immune systems of other species and variation within the order affect primate disease susceptibility, infectious disease emergence, and human health. There is, however, limited information on differences in baseline immune function within the primate order. As such, a comparative immunological review of vertebrate immunity can offer insight into the evolutionary divergence of primate immune system function. The goal of this chapter is to provide an evolutionary background for the development and diversification of the primate immune system. Here, we put primate immunity in the context of the emergence of the major structures and cellular components and the vertebrate immune system over evolutionary time with special attention paid, when information is available, to examples of how baseline immunity has diverged between primate species.

Section I Immunity and Primate Evolution Vertebrate Immune system evolution and comparative primate immunity Jessica F. Brinkworth and Mitchell Thorn Genetic variation in the immune system of Old World monkeys: functional and selective effects Dagan A. Loisel and Jenny Tung Toll-like receptor function and evolution in primates Jessica F. Brinkworth and Kirstin N. Sterner Impact of natural selection due to malarial disease on human genetic variation Felicia Gomez, Wen-Ya Ko, Avery Davis, and Sarah A. Tishkoff Parasitic lice help to fill in the gaps of early hominid history Julie M. Allen, Cedric O. Worman, Jessica E. Light, and David L. Reed Section II Emergence and Divergent Disease Manifestation Treponema pallidum infection in Primates: Clinical Manifestations, Epidemiology, and Evolution of a Stealthy Pathogen Kristin Harper and Sascha Knauf Molecular mimicry by i -2 herpesviruses to modulate host cell signaling pathways Lai-Yee Wong, Zsolt toth, Kevin F. Brulois, Kyung-Soo Inn, Sun-Hwa Lee, Hye-Ra Lee, and Jae U. Jung Neotropical primates and their susceptibility to Toxoplasma gondii: new insights for an old problem Jose Luiz Catao-Dias, Sabrina Epiphanio and Maria Cecilia Martins Kierulff The Evolution of SIV in primates and the emergence of the pathogen of AIDS Edward JD Greenwood, Fabian Schmidt, and Jonathan L. Heeney Section III Primates, Pathogens and Health Microbial exposures and other early childhood influences on the subsequent function of the immune system Graham A.W. Rook. Make new friends and keep the old? Parasite coinfection and comorbidity in Homo sapiens Melanie Martin, Aaron D. Blackwell, Michael Gurven and Hillard Kaplan Primates, pathogens and evolution: A context for understanding emerging disease Kristin N. Harper, Molly K. Zuckerman, Bethany L. Turner, George Armelagos

Toll-like receptors (TLRs) are an important interface between vertebrate hosts and pathogens. From an evolutionary standpoint, these germline encoded receptors and their associated signaling pathways are interesting because they provide a window through which we can examine the relationships between primate environments, genomes, and immune responses. TLRs are key in host recognition of nonself and the activation of the innate immune response, a major determinant of host infection susceptibility and disease progression. TLR-initiated cell signaling not only forms an important part of host’s first line of defense against immune insult but also modulates adaptive immune responses. The efficacy of TLR-triggered immune responses has profound effects on host survival, with both overt and weak responses linked to host death. Despite sharing high genomic identity, primate species often manifest TLR-detected infectious pathogens differently (e.g., immunodeficiency viruses, Trypanosoma brucei, and Gram-negative bacteria). These differences suggest that primate TLR-triggered responses have diverged over time. In this chapter we review what is currently known about Toll-like receptor function and evolution in primates and discuss how studying the evolution of TLR-triggered immune responses may help explain disparities observed in microorganism-induced primate disease.

Pathogens are a major force affecting the evolution of mammals. In primates, strong interspecies differences in disease susceptibility, progression, and survival after exposure to particular pathogens such as immunodeficiency viruses, Plasmodium, Trypanosoma, herpesvirus suggests the existence of species-specific pathogen-associated selective pressures in the past. Despite increasing recognition that the immune systems of particular primates have evolved to respond to unique challenges, we have a fairly superficial understanding of differences in primate immune function, primate–pathogen molecular interaction, and pathogen–primate coevolution. Research in this field is hindered by a lack of interdisciplinary and cross-field integration, a focus on a limited number of pathogens, and the separation of research on primate molecular evolution and primate immune function. To better understand human and nonhuman primate evolution, immune function, and susceptibility to infectious disease, a synthesis of research on the pathogen-related evolution and biochemical mechanisms of primate interaction with a broad range of microorganisms is required. A comprehensive model of how primates and pathogens have coevolved is crucial, as interspecies differences in primate–pathogen molecular interaction play a role in the emergence of pandemic human pathogens (HIV–1/HIV-2, malaria/Plasmodium, and lice) and affect the sustainability of primate populations (Toxoplasma and Mycobacterium), the utility of primate biomedical models, and the evolution of primate genomes.