9 research outputs found
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Selective expansion of myeloid and NK cells in humanized mice yields human-like vaccine responses
Mice engrafted with components of a human immune system have become widely-used models for studying aspects of human immunity and disease. However, a defined methodology to objectively measure and compare the quality of the human immune response in different models is lacking. Here, by taking advantage of the highly immunogenic live-attenuated yellow fever virus vaccine YFV-17D, we provide an in-depth comparison of immune responses in human vaccinees, conventional humanized mice, and second generation humanized mice. We demonstrate that selective expansion of human myeloid and natural killer cells promotes transcriptomic responses akin to those of human vaccinees. These enhanced transcriptomic profiles correlate with the development of an antigen-specific cellular and humoral response to YFV-17D. Altogether, our approach provides a robust scoring of the quality of the human immune response in humanized mice and highlights a rational path towards developing better pre-clinical models for studying the human immune response and disease.National Institute of General Medical Sciences (U.S.) (Award T32GM007753)Searle Scholars ProgramArnold and Mabel Beckman Foundation (Young Investigator Program)National Institutes of Health (U.S.) (1DP2OD020839)National Institutes of Health (U.S.) (5U24AI118672)National Institutes of Health (U.S.) (1U54CA217377)National Institutes of Health (U.S.) (1R33CA202820)National Institutes of Health (U.S.) (2U19AI089992)National Institutes of Health (U.S.) (21R01HL134539)National Institutes of Health (U.S.) (2RM1HG006193)National Institutes of Health (U.S.) (2R01HL095791)National Institutes of Health (U.S.) (P01AI039671)Bill & Melinda Gates Foundation (OPP1139972
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Differences across cyclophilin A orthologs contribute to the host range restriction of hepatitis C virus.
The restricted host tropism of hepatitis C virus (HCV) remains incompletely
understood, especially post-entry, and has hindered developing an immunocompetent, small animal
model. HCV replication in non-permissive species may be limited by incompatibilities between the
viral replication machinery and orthologs of essential host factors, like cyclophilin A (CypA). We
thus compared the ability of CypA from mouse, tree shrew, and seven non-human primate species
to support HCV replication, finding that murine CypA only partially rescued viral replication in
Huh7.5-shRNA CypA cells. We determined the specific amino acid differences responsible and
generated mutants able to fully rescue replication. We expressed these mutants in engineered
murine hepatoma cells and although we observed increases in HCV replication following infection,
they remained far lower than those in highly permissive human hepatoma cells, and minimal
infectious particle release was observed. Together, these data suggest additional co-factors remain
unidentified. Future work to determine such factors will be critical for developing an
immunocompetent mouse model supporting HCV replication
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Conservation of cell-intrinsic immune responses in diverse nonhuman primate species.
Differences in immune responses across species can contribute
to the varying permissivity of species to the same viral pathogen.
Understanding how our closest evolutionary relatives, nonhuman
primates (NHPs), confront pathogens and how these responses
have evolved over time could shed light on host range barriers,
especially for zoonotic infections. Here, we analyzed cell-intrinsic
immunity of primary cells from the broadest panel of NHP species
interrogated to date, including humans, great apes, and Old and
New World monkeys. Our analysis of their transcriptomes after
poly(I:C) transfection revealed conservation in the functional
consequences of their response. In mapping reads to either the
human or the species-specific genomes, we observed that with
the current state of NHP annotations, the percent of reads
assigned to a genetic feature was largely similar regardless of the
method. Together, these data provide a baseline for the cellintrinsic responses elicited by a potent immune stimulus across
multiple NHP donors, including endangered species, and serve as
a resource for refining and furthering the existing annotations of
NHP genomes
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Species-specific disruption of STING-dependent antiviral cellular defenses by the Zika virus NS2B3 protease.
The limited host tropism of numerous viruses causing disease in
humans remains incompletely understood. One example is Zika
virus (ZIKV), an RNA virus that has reemerged in recent years.
Here, we demonstrate that ZIKV efficiently infects fibroblasts from
humans, great apes, New and Old World monkeys, but not
rodents. ZIKV infection in human—but not murine—cells impairs
responses to agonists of the cGMP-AMP synthase/stimulator of IFN
genes (cGAS/STING) signaling pathway, suggesting that viral
mechanisms to evade antiviral defenses are less effective in rodent
cells. Indeed, human, but not mouse, STING is subject to cleavage
by proteases encoded by ZIKV, dengue virus, West Nile virus, and
Japanese encephalitis virus, but not that of yellow fever virus. The
protease cleavage site, located between positions 78/79 of human
STING, is only partially conserved in nonhuman primates and rodents, rendering these orthologs resistant to degradation. Genetic
disruption of STING increases the susceptibility of mouse—but not
human—cells to ZIKV. Accordingly, expression of only mouse, not
human, STING in murine STING knockout cells rescues the ZIKV
suppression phenotype. STING-deficient mice, however, did not
exhibit increased susceptibility, suggesting that other redundant
antiviral pathways control ZIKV infection in vivo. Collectively, our
data demonstrate that numerous RNA viruses evade cGAS/STINGdependent signaling and affirm the importance of this pathway in
shaping the host range of ZIKV. Furthermore, our results explain—
at least in part—the decreased permissivity of rodent cells to ZIKV,
which could aid in the development of mice model with inheritable susceptibility to ZIKV and other flaviviruses
Recommended from our members
Species-specific disruption of STING-dependent antiviral cellular defenses by the Zika virus NS2B3 protease
The limited host tropism of numerous viruses causing disease in
humans remains incompletely understood. One example is Zika
virus (ZIKV), an RNA virus that has reemerged in recent years.
Here, we demonstrate that ZIKV efficiently infects fibroblasts from
humans, great apes, New and Old World monkeys, but not
rodents. ZIKV infection in human—but not murine—cells impairs
responses to agonists of the cGMP-AMP synthase/stimulator of IFN
genes (cGAS/STING) signaling pathway, suggesting that viral
mechanisms to evade antiviral defenses are less effective in rodent
cells. Indeed, human, but not mouse, STING is subject to cleavage
by proteases encoded by ZIKV, dengue virus, West Nile virus, and
Japanese encephalitis virus, but not that of yellow fever virus. The
protease cleavage site, located between positions 78/79 of human
STING, is only partially conserved in nonhuman primates and rodents, rendering these orthologs resistant to degradation. Genetic
disruption of STING increases the susceptibility of mouse—but not
human—cells to ZIKV. Accordingly, expression of only mouse, not
human, STING in murine STING knockout cells rescues the ZIKV
suppression phenotype. STING-deficient mice, however, did not
exhibit increased susceptibility, suggesting that other redundant
antiviral pathways control ZIKV infection in vivo. Collectively, our
data demonstrate that numerous RNA viruses evade cGAS/STINGdependent signaling and affirm the importance of this pathway in
shaping the host range of ZIKV. Furthermore, our results explain—
at least in part—the decreased permissivity of rodent cells to ZIKV,
which could aid in the development of mice model with inheritable susceptibility to ZIKV and other flaviviruses
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Isocotoin suppresses hepatitis E virus replication through inhibition of heat shock protein 90
Hepatitis E virus (HEV) causes 14 million infections and 60,000 deaths per year globally, with
immunocompromised persons and pregnant women experiencing severe symptoms. Although
ribavirin can be used to treat chronic hepatitis E, toxicity in pregnant patients and the emergence
of resistant strains are major concerns. Therefore there is an imminent need for effective HEV
antiviral agents. The aims of this study were to develop a drug screening platform and to discover
novel approaches to targeting steps within the viral life cycle. We developed a screening platform
for molecules inhibiting HEV replication and selected a candidate, isocotoin. Isocotoin inhibits
HEV replication through interference with heat shock protein 90 (HSP90), a host factor not
previously known to be involved in HEV replication. Additional work is required to understand the compound’s translational potential, however this suggests that HSP90-modulating molecules,
which are in clinical development as anti-cancer agents, may be promising therapies against HEV
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Hepatitis C virus infects rhesus macaque hepatocytes and simianized mice
At least 170 million people are chronically infected with hepatitis C virus (HCV). Due to the narrow host range of HCV and restricted use of chimpanzees, there is currently no suitable animal model for HCV pathogenesis studies or the development of a HCV vaccine. To identify cellular determinants of interspecies transmission and establish a novel immunocompetent model system, we examined the ability of HCV to infect hepatocytes from a small non-human primate, the rhesus macaque (Macaca mulatta). We show that the rhesus orthologs of critical HCV entry factors support viral glycoprotein-dependent virion uptake. Primary hepatocytes from rhesus macaques are also permissive for HCV RNA replication and particle production, which is enhanced when antiviral signaling is suppressed. We demonstrate that this may be due to the diminished capacity of HCV to antagonize MAVS-dependent innate cellular defenses. To test the ability of HCV to establish persistent replication in vivo, we engrafted primary rhesus macaque hepatocytes into immunocompromised xenorecipients. Inoculation of resulting simian liver chimeric mice with either HCV genotype 1a or 2a resulted in HCV serum viremia for up to 10 weeks. Conclusion: Together, these data indicate that rhesus macaques may be a viable model for HCV and implicate host immunity as a potential species-specific barrier to HCV infection. We conclude that suppression of host immunity or further viral adaptation may allow robust HCV infection in rhesus macaques and creation of a new animal model for studies of HCV pathogenesis, lentivirus coinfection and vaccine development
Recommended from our members
Hepatitis C virus infects rhesus macaque hepatocytes and simianized mice
At least 170 million people are chronically infected with hepatitis C virus (HCV). Due to the
narrow host range of HCV and restricted use of chimpanzees, there is currently no suitable animal
model for HCV pathogenesis studies or the development of a HCV vaccine. To identify cellular
determinants of interspecies transmission and establish a novel immunocompetent model system,
we examined the ability of HCV to infect hepatocytes from a small non-human primate, the rhesus
macaque (Macaca mulatta). We show that the rhesus orthologs of critical HCV entry factors
support viral glycoprotein-dependent virion uptake. Primary hepatocytes from rhesus macaques
are also permissive for HCV RNA replication and particle production, which is enhanced when
antiviral signaling is suppressed. We demonstrate that this may be due to the diminished capacity
of HCV to antagonize MAVS-dependent innate cellular defenses. To test the ability of HCV to
establish persistent replication in vivo, we engrafted primary rhesus macaque hepatocytes into immunocompromised xenorecipients. Inoculation of resulting simian liver chimeric mice with
either HCV genotype 1a or 2a resulted in HCV serum viremia for up to 10 weeks. Conclusion:
Together, these data indicate that rhesus macaques may be a viable model for HCV and implicate
host immunity as a potential species-specific barrier to HCV infection. We conclude that
suppression of host immunity or further viral adaptation may allow robust HCV infection in
rhesus macaques and creation of a new animal model for studies of HCV pathogenesis, lentivirus
coinfection and vaccine development