Comparative analyses across diverse bat families suggest evolution of complementary adaptations that enhance antiviral tolerance and dampen inflammation.Mathematical and computational modeling have ...helped uncover unanticipated factors, such as the role of the endothelial inflammasome in bat resistance to viral load.Single cell transcriptome sequencing is providing detailed, spatial information on critical immune cell populations in bats relative to other mammals and how these cell types respond to virus infection.Generation of bat induced pluripotent stem cells reveals remarkable variety and activity of retroviruses and endogenous virus sequences, indicating that bats have evolved mechanisms to tolerate high viral loads.
Bats are among the most diverse of all mammalian species and serve as reservoirs of zoonotic viruses responsible for several recent pandemics. Understanding the multiple and complex factors that drive the evolution of viruses and their hosts is crucial for better understanding mammalian and human immunity, as well as for anticipating and preparing for future pandemics. New technologies are providing insights into how the unique physiology and lifestyle of bats drive tolerance to virus infection.
Bats are among the most diverse mammalian species, representing over 20% of mammalian diversity. The past two decades have witnessed a disproportionate spillover of viruses from bats to humans compared with other mammalian hosts, attributed to the viral richness within bats, their phylogenetic likeness to humans, and increased human contact with wildlife. Unique evolutionary adaptations in bat genomes, particularly in antiviral protection and immune tolerance genes, enable bats to serve as reservoirs for pandemic-inducing viruses. Here, we discuss current limitations and advances made in understanding the role of bats as drivers of pandemic zoonoses. We also discuss novel technologies that have revealed spatial, dynamic, and physiological factors driving virus and host coevolution.
Bats are among the most diverse mammalian species, representing over 20% of mammalian diversity. The past two decades have witnessed a disproportionate spillover of viruses from bats to humans compared with other mammalian hosts, attributed to the viral richness within bats, their phylogenetic likeness to humans, and increased human contact with wildlife. Unique evolutionary adaptations in bat genomes, particularly in antiviral protection and immune tolerance genes, enable bats to serve as reservoirs for pandemic-inducing viruses. Here, we discuss current limitations and advances made in understanding the role of bats as drivers of pandemic zoonoses. We also discuss novel technologies that have revealed spatial, dynamic, and physiological factors driving virus and host coevolution.
Regulation of catalytic activity of E3 ubiquitin ligases is critical for their cellular functions. We identified an unexpected mode of regulation of E3 catalytic activity by ions and osmolarity; ...enzymatic activity of the HECT family E3 Nedd4-2/Nedd4L is enhanced by increased intracellular Na
(Na
) and by hyperosmolarity. This stimulated activity is mediated by activation of p38-MAPK and is inhibited by WNKs. Moreover, protease (Furin)-mediated activation of the epithelial Na
channel ENaC (a bona fide Nedd4-2 substrate), which leads to increased Na
and osmolarity, results in enhanced Nedd4-2 catalytic activity. This enhancement is inhibited by a Furin inhibitor, by a protease-resistant ENaC mutant, or by treatment with the ENaC inhibitor amiloride. Moreover, WNK inhibition, which stimulates catalytic activity of Nedd4-2, leads to reduced levels of cell-surface ENaC and reduced channel activity. ENaC activity does not affect Nedd4-2:ENaC binding. Therefore, these results demonstrate activation of a ubiquitin ligase by Na
and osmotic changes. Importantly, they reveal a negative feedback loop in which active ENaC leads to stimulation of catalytic activity of its own suppressor, Nedd4-2, to protect cells from excessive Na
loading and hyperosmotic stress and to protect the animal from hypertension.
mTORC1 regulates cellular growth and is activated by growth factors and by essential amino acids such as Leu. Leu enters cells via the Leu transporter LAT1-4F2hc (LAT1). Here we show that the ...Na+/K+/2Cl− cotransporter NKCC1 (SLC12A2), a known regulator of cell volume, is present in complex with LAT1. We further show that NKCC1 depletion or deletion enhances LAT1 activity, as well as activation of Akt and Erk, leading to activation of mTORC1 in cells, colonic organoids, and mouse colon. Moreover, NKCC1 depletion reduces intracellular Na+ concentration and cell volume (size) and mass and stimulates cell proliferation. NKCC1, therefore, suppresses mTORC1 by inhibiting its key activating signaling pathways. Importantly, by linking ion transport and cell volume regulation to mTORC1 function, NKCC1 provides a long-sought link connecting cell volume (size) to cell mass regulation.
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•The ion transporter NKCC1 forms a complex with the Leu transporter LAT1•NKCC1 inhibits LAT1 function and Akt and Erk signaling, suppressing mTORC1 activation•NKCC1 depletion reduces Na+i and cell volume and enhances cell proliferation•NKCC1 links the regulation of cell volume (size) to cell mass
Demian et al. show that the Na/K/2Cl ion transporter NKCC1, a known regulator of cell volume, inhibits the Leu transporter LAT1 and the Akt/Erk pathways, thus inhibiting mTORC1 activation and providing a link between cell volume (size) and cell mass regulation.
Isolating and characterizing emerging SARS-CoV-2 variants is key to understanding virus pathogenesis. In this study, we isolated samples of the SARS-CoV-2 R.1 lineage, categorized as a variant under ...monitoring by the World Health Organization, and evaluated their sensitivity to neutralizing antibodies and type I interferons. We used convalescent serum samples from persons in Canada infected either with ancestral virus (wave 1) or the B.1.1.7 (Alpha) variant of concern (wave 3) for testing neutralization sensitivity. The R.1 isolates were potently neutralized by both the wave 1 and wave 3 convalescent serum samples, unlike the B.1.351 (Beta) variant of concern. Of note, the R.1 variant was significantly more resistant to type I interferons (IFN-α/β) than was the ancestral isolate. Our study demonstrates that the R.1 variant retained sensitivity to neutralizing antibodies but evolved resistance to type I interferons. This critical driving force will influence the trajectory of the pandemic.
Apoptosis signal-regulating kinase 1 (ASK1)/MAP3K5 is a stress response kinase that is activated by various stimuli. It is known as an upstream activator of p38- Mitogen-activated protein kinase ...(p38MAPK) and c-Jun N-terminal kinase (JNK) that are reactive oxygen species (ROS)-induced kinases. Accumulating evidence show that ROS accumulate in virus-infected cells. Here, we investigated the relationship between viruses and ASK1/p38MAPK or ASK1/JNK pathways. Our findings suggest that virus infection activates ASK1 related pathways. In parallel, ASK1 inhibition led to a remarkable reduction in the replication of a broad range of viruses including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), vaccinia virus (VV), vesicular stomatitis virus (VSV), Herpes Simplex Virus (HSV), and Human Immunodeficiency virus (HIV) in different human cell lines. Our work demonstrates the potential therapeutic use of Selonsertib, an ASK1 inhibitor, as a pan-antiviral drug in humans. Surprisingly, we observed differential effects of Selonsertib in in vitro and in vivo hamster models, suggesting caution in using rodent models to predict clinical and therapeutic outcomes in humans.
Type I interferons (IFNs) are our first line of defense against virus infection. Recent studies have suggested the ability of SARS-CoV-2 proteins to inhibit IFN responses. Emerging data also suggest ...that timing and extent of IFN production is associated with manifestation of COVID-19 severity. In spite of progress in understanding how SARS-CoV-2 activates antiviral responses, mechanistic studies into wild-type SARS-CoV-2-mediated induction and inhibition of human type I IFN responses are scarce. Here we demonstrate that SARS-CoV-2 infection induces a type I IFN response in vitro and in moderate cases of COVID-19. In vitro stimulation of type I IFN expression and signaling in human airway epithelial cells is associated with activation of canonical transcriptions factors, and SARS-CoV-2 is unable to inhibit exogenous induction of these responses. Furthermore, we show that physiological levels of IFNα detected in patients with moderate COVID-19 is sufficient to suppress SARS-CoV-2 replication in human airway cells.
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•SARS-CoV-2 induces the expression of type I IFNs in human lung cells•Moderate cases of COVID-19 have higher serum levels of IL-10 and IFNα•Severe cases of COVID-19 have higher serum levels of IL-6, TNFα and IL-8•Physiological levels of IFNα reduces SARS-CoV-2 replication in human airway cells
Immunology; Virology
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