A Potent Anti-Inflammatory Response in Bat Macrophages May Be Linked to Extended Longevity and Viral Tolerance

Abstract

Bats are unique among mammals given their ability to fly, apparent tolerance of deadly viruses and extraordinary longevity. We propose that these traits are linked and driven by adaptations of the innate immune system. To explore this hypothesis we challenged macrophages from the greater mouse-eared bat, Myotis myotis and the house mouse, Mus musculus with Toll Like Receptors (TLRs) ligands, lipopolysaccharides, LPS and polyinosinic-polycytidylic acid, Poly(I:C). Macrophages from both species presented a high level of mRNA induction of inferon β (INF-β), tumor necrosis factor (TNF) and interleukin-1β (Il-1β). However, in bat macrophages, this antiviral, proinflammatory response was balanced by a sustained high-level transcription of the anti-inflammatory cytokine Il-10, which was not observed in mouse, potentially resulting from adaptive regulation in bats.Additionally, phylogenomic selection tests across the basal divergences in mammals (n = 39) uncovered bat-specific adaptations in six genes involved in antiviral and proinflammatory signalling. Based on this pilot study, we put forward a hypothesis that bats may have evolved unique anti-inflammatory responses to neutralize proinflammatory stimuli resulting from flight. This in turn may drive their extraordinary longevity and viral tolerance by limiting inflammation driven ageing and infection-induced immunopathology. Further data from other individuals and bat species are required to advance this intriguing hypothesis.

Novel Insights Into Immune Systems of Bats

“…Strong and chronic inflammation has been associated with poor disease prognosis and health issues in humans and other susceptible animal models (53,54). The ability of bats to control high levels of inflammation may also explain their long life span (55,56) in addition to their ability to host (57) multiple viruses in the absence of clinical disease. Similar studies on virus-host interactions in bats are allowing researchers to understand the evolution of antiviral responses in mammals and underlying factors that lead to lethal disease outcomes in humans upon infection with emerging batborne viruses.…”

Bat Biology, Genomes, and the Bat1K Project: To Generate Chromosome-Level Genomes for All Living Bat Species

“…Bats have enhanced immune function, coupled with a potentially modulated inflammatory response (11,16,47). This holds considerable potential for addressing some of the worst consequences of senescence of humans.…”

“…Epidemiological studies and field surveys suggest viruses circulate in wild bat populations (12,55) without causing the great morbidity or mortality observed as a result of viral spillovers into humans (Table 1) (14,56). Although the processes through which bats manage to clear viral infections remain poorly understood, possible explanations for the resilience of individual bats to these infections include not only heightened immune function but modulation of inflammation and mechanisms of repair (16). Genomic analyses have already revealed coevolution with viruses as a long-term consequence of bat evolution (57).…”

“…The ability to modulate inappropriate inflammation in response to stressors without impairing immune function could improve the lives of millions. Hence, detailed exploration of the genomic mechanisms of gene expression in wild bats could hold the key to improving health conditions worldwide (16). High-quality bat genomes will drive a better understanding of molecular bases underlying the resistance/tolerance of European bats to white-nose syndrome (49), which could ultimately be used to inform future bat conservation and management efforts within the United States.…”

“…Bats are suspected reservoirs for some of the deadliest viral diseases [e.g., Ebola, SARS (severe acute respiratory syndrome), rabies, and MERS (Middle East respiratory syndrome coronavirus); [11][12][13][14], but they appear to be asymptomatic and survive these infections. This suggests that bats have evolved unique immune systems, and potentially the solution to better tolerate these pathogens may lie in uncovering how bats limit their immunopathology upon infection (15,16). Bats also exhibit extraordinary longevity-they can live up to 10 times longer than expected given their small body size and high metabolic rate (17).…”