Bats host the most virulent—but not the most dangerous—zoonotic viruses

Abstract

Identifying virus characteristics associated with the largest public health impacts on human populations is critical to informing zoonotic risk assessments and surveillance strategies. Efforts to assess "zoonotic risk" often use trait-based analyses to identify which viral and reservoir host groups are most likely to source zoonoses but have not fully addressed how and why the impacts of zoonotic viruses vary in terms of disease severity ('virulence'), capacity to spread within human populations ('transmissibility'), or total human mortality ('death burden'). We analyzed trends in human case fatality rates, transmission capacities, and total death burdens across a comprehensive dataset of mammalian and avian zoonotic viruses. Bats harbor the most virulent zoonotic viruses even when compared to birds, which alongside bats, have been hypothesized to be "special" zoonotic reservoirs due to molecular adaptations that support the physiology of flight. Reservoir host groups more closely related to humans—in particular, Primates—harbor less virulent, but more highly transmissible viruses. Importantly, disproportionately high human death burden, arguably the most important metric of zoonotic risk, is not associated with any animal reservoir, including bats. Our data demonstrate that mechanisms driving death burdens are diverse and often contradict trait-based predictions. Ultimately, total human mortality is dependent on context-specific epidemiological dynamics, which are shaped by a combination of viral traits and conditions in the animal host population and across and beyond the human-animal interface. Understanding the conditions that predict high zoonotic burden in humans will require longitudinal studies of epidemiological dynamics in wildlife and human populations.

Reservoir host immunology and life history shape virulence evolution in zoonotic viruses

“…Records of avirulent zoonoses are rare for other taxa, excepting Primates, which are also well-studied, and Cetartiodactyla, for which existing data on zoonotic viruses are derived entirely from domesticated livestock 4 . Our model's overprediction of virus virulence from Cetartiodactyla squares with hypotheses that the low virulence of zoonoses recorded for this clade may reflect higher research effort and sampling rates for livestock pathogens (thus minimizing attainment bias)-or that centuries of human-livestock cohabitation and development of human immunity to livestock pathogens could have muted the virulence of Cetartiodactyla viruses in human hosts 4 .…”

“…Top panel depicts human 𝛼 $ predictions by order, derived from within-host model, using order-specific parameters for 𝜇, 𝑇 & , 𝜌, 𝑇 %$ computed from life history traits in (a), (b), and (c). Bottom panel depicts human 𝛼 $ estimates derived from case fatality rates and infection duration reported in the zoonotic literature 4 . Point size corresponds to the average of the number of species-level datapoints (N) used to generate each of the four variable parameters impacting 𝛼 $ for top panel and to the number of independent host-virus associations from which estimates were determined for bottom panel.…”

“…Figure replicates Fig.3d(main text) under assumptions of complete tolerance. Top panel depicts 𝛼 $ in human predictions for zoonoses by order, derived from our nested within-host, life history model, while bottom panel depicts human 𝛼 $ estimates derived from case fatality rates and infection duration reported in the zoonotic literature4 . For predictions, point size corresponds to the average of the number of species-level datapoints (N) used to generate each of the four variable parameters (Fig.3, Extended Data Fig.3) used in human 𝛼 $ predictions.…”

“…Predicting the virulence of an emerging virus is a complex problem since chance will always play a role in dictating the initial spillover that precedes selection 1 , virulence upon emergence may be maladaptive in novel hosts 2,3 , and patterns in available data may be muddled by attainment bias if avirulent infections go underreported 1 . Nonetheless, reservoir host immunological and life history traits may be important drivers of cross-species virus virulence; bats, in particular, host viruses that cause higher human case fatality rates than zoonoses derived from other mammals and birds 4,5 . Understanding the mechanisms that select for the evolution of unique viral traits in bats compared to those selected in other mammalian reservoirs is essential to accurately predicting virulence for future zoonotic threats.Although the disproportionate frequency with which the Chiropteran order may source viral zoonoses remains debated 6,7 , the extraordinary human pathology induced by many batborne zoonoses-including Ebola and Marburg filoviruses, Hendra and Nipah henipaviruses, and SARS, MERS, and SARS-CoV-2 coronaviruses 8 -is not contested.…”

“…5) 4 : though most rabies zoonoses are sourced from domestic dogs, lyssaviruses are Chiropteran by origin 25 , and viral traits responsible for rabies' virulence may reflect its bat evolutionary history more than that of any intermediate carnivore host. For Rodentia, comparatively lower spillover virulence reported in the literature suggests that attainment bias may be less extreme for this clade: rodent-borne hantaviruses and arenaviruses represent some of the best-studied zoonoses, and multiple avirulent species within these families are referenced in our dataset 4 . Records of avirulent zoonoses are rare for other taxa, excepting Primates, which are also well-studied, and Cetartiodactyla, for which existing data on zoonotic viruses are derived entirely from domesticated livestock 4 .…”