Biology subjects

Uhrlaub, J. L.

Publications and source records attributed to Uhrlaub, J. L..

7 recordsLinked to original sources

bioRxiv2024

Chronic Toxoplasma gondii infection curtails the cytotoxic potential of acute T cell responses to West Nile virus in the brain.

Toxoplasma gondii (T. gondii), a common brain-tropic parasite, chronically infects the central nervous system (CNS) of up to a third of the worlds population. Constant immune surveillance interrupts cyst reactivation within the CNS and dramatically alters the immune landscape of the brain. West Nile virus (WNV) is a mosquito-borne infection with a clinical spectrum ranging from asymptomatic to mild flu-like symptoms to severe neuroinvasive disease. In a cohort of WNV infected people, we discovered a positive correlation between WNV disease severity and T. gondii seropositivity. In a mouse model pairing chronic T. gondii with acute WNV infection, we found an increased susceptibility of mice to WNV, with reduced granzyme B expression in WNV-specific T cells and increased regulatory T cell (Treg) numbers in the brain, but not the periphery. This demonstrates that the T. gondii-infected tissue microenvironment impairs immune defense against other brain infections by blunting local T cell responses.

immunology↗

bioRxiv2023

Characterization of low copy number human angiotensin-convertase 2 (hACE2)-transgenic mice as an improved model of SARS-CoV-2 infection

Coronaviridae are significant human pathogens, as evidenced by several outbreaks of severe respiratory infections in the past 20 years and culminating with the COVID-19 pandemic. Mouse models of COVID-19 have included transgenic expression of the main SARS coronavirus entry receptor on human cells, human angiotensin-converting enzyme 2 (hACE2). However, the original hACE2-Tg mouse strain overexpresses many copies of the transgene, leading to neuropathology not representative of human infection. Aiming to improve physiological relevance, we generated two new lines of hACE2-Tg mice using the original transgene construct expressing hACE2 under the control of the keratin 18 promoter (K18-hACE2). We show that relative to the original strain, which expressed 8 copies of the transgene (8-hACE2-Tg), lines 1 and 2 expressed 1 and 2 copies of the transgene (1-hACE-2-Tg and 2-hACE-2-Tg, respectively). Upon intranasal (i.n.) infection with 103 plaque-forming units (pfu) SARS-CoV-2 WA-1/US, 8-hACE2-Tg mice succumbed to infection by d. 7. 2-hACE2-Tg mice exhibited 31% survival, with less viral replication in the lung and brain when compared to 8-hACE2-Tg mice. Furthermore, SARS-CoV-2 infection in 1-hACE2-Tg mice exhibited no mortality and had no detectable virus in the brain, although they did show clear virus replication in the lung. All three mouse strains analyzed showed SARS-CoV-2-related weight loss that tracked with the mortality rates. 1-hACE2-Tg mice mounted detectable primary and memory T effector cell and antibody responses. We conclude that these strains, particularly 1-hACE2-Tg mice, provide improved models to study hACE2-mediated viral infections.

immunology↗

bioRxiv2021

LIFELONG CYTOMEGALOVIRUS AND EARLY-LIFE IRRADIATION SYNERGISTICALLY POTENTIATE AGE-RELATED DEFECTS IN RESPONSE TO VACCINATION AND INFECTION

A popular "DNA-damage theory" of aging posits that unrepaired DNA damage leads to cellular (and organismal) senescence. Indeed, some hallmarks of immune aging are more prevalent in individuals exposed to Whole-Body Irradiation (WBI). To test this hypothesis in a model relevant to human immune aging, we examined separate and joint effects of lifelong latent Murine Cytomegalovirus (MCMV) and early-life WBI (i) over the course of the lifespan; (ii) in response to a West Nile virus (WNV) live attenuated vaccine; and (iii) following lethal WNV challenge subsequent to vaccination. We recently published that a single dose of non-lethal WBI in youth, on its own, was not sufficient to accelerate aging of the murine immune system despite causing widespread DNA damage and repopulation stress in hematopoietic cells. However, 4Gy sub-lethal WBI caused manifest reactivation of MCMV. Following vaccination and challenge with WNV in the old age, MCMV-infected animals experiencing 4Gy, but not lower, dose of sub-lethal WBI in youth had reduced survival. By contrast, old irradiated mice lacking MCMV and MCMV-infected, but not irradiated, mice were both protected to the same high level as the old non-irradiated, uninfected controls. Analysis of the quality and quantity of anti-WNV immunity showed that higher mortality in MCMV-positive WBI mice correlated with increased levels of MCMV-specific immune activation during WNV challenge. Moreover, we demonstrate that infection, including that by WNV, led to MCMV reactivation. Our data suggest that MCMV reactivation may be an important determinant of increased late-life mortality following early-life irradiation and late-life acute infection.

immunology↗

bioRxiv2021

The impact of murine cytomegalovirus (mCMV) route and age at infection upon virus spread, immune responses and the establishment of latency

Cytomegalovirus (CMV) is a ubiquitous human virus, which establishes a characteristic lifetime infection in its host. Murine CMV (mCMV) is a widely-used infection model that has been employed to investigate the nature and extent of CMVs contribution to inflammatory, immunological, and health disturbances in humans. In an effort to assess the role of route and age in modeling hCMV infection in mice, we have performed a comparative analysis of two common experimental modes of infection (intraperitoneal and intranasal) at two different clinically relevant ages (4 weeks, or prepubescent childhood equivalent, and 12 weeks, or young postpubescent adult). We found that while both routes of infection led to similar early viral loads, differential activation of several parameters of innate immune function were observed. In particular, younger, prepubescent mice exhibited the strongest NK activation in the blood in response to i.p. infection, with this trend holding true in NK cells expressing the mCMV-specific receptor Ly49H. Moreover, i.p. infected animals accumulated a larger amount of anti-mCMV IgG and experienced a greater expansion of both acute and latent phase CD8+ T cells. This was especially true for young postpubescent mice, further illustrating a distinction in the bloodborne immune response across not only infection routes, but also ages. These results may be important in the understanding of how a more physiologically applicable model of CMV influences immunity, inflammation, and health over the lifespan.

immunology↗

bioRxiv2021

Early age-related atrophy of cutaneous lymph nodes precipitates an early functional decline in skin immunity in mice with aging

Secondary lymphoid organs (SLO; including the spleen and lymph nodes) are critical both for the maintenance of naive T (TN) lymphocytes and for the initiation and coordination of immune responses. How they age, including the exact timing, extent, physiological relevance, and the nature of age-related changes, remains incompletely understood. We used time-stamping to indelibly mark cohorts of newly generated naive T cells (a.k.a. recent thymic emigrants - RTE) in mice, and followed their presence, phenotype and retention in SLO. We found that SLO involute asynchronously. Skin-draining lymph nodes (LN) atrophied early (6-9 months) in life and deeper tissue-draining LN and the spleen late (18-20 months), as measured by the loss of both TN numbers and the fibroblastic reticular cell (FRC) network. Time-stamped RTE cohorts of all ages entered SLO and successfully completed post-thymic differentiation. However, in older mice, these cells were poorly retained, and those found in SLO exhibited an emigration phenotype (CCR7loS1P1hi). Transfers of adult RTE into recipients of different ages formally demonstrated that the defect segregates with the age of the SLO microenvironment and not with the age of T cells. Finally, upon intradermal immunization, RTE generated in mice as early as 6-7 months of age barely participated in de novo immune responses and failed to produce well-armed effector cells. These results highlight changes in structure and function of superficial secondary lymphoid organs in laboratory mice that are earlier than expected and are consistent with the long-appreciated and pronounced reduction of cutaneous immunity with aging.

immunology↗

bioRxiv2021

Competent immune responses to SARS-CoV-2 variants in older adults following mRNA vaccination

Aging is associated with a reduced magnitude of primary immune responses to vaccination and constriction of immune receptor repertoire diversity. Clinical trials demonstrated high efficacy of mRNA based SARS-CoV-2 vaccines in older adults but concerns about virus variant escape have not been well addressed. We have conducted an in-depth analysis of humoral and cellular immunity against an early-pandemic viral isolate and compared that to the P.1. (Gamma) and B.1.617.2 (Delta) variants in <50 and >55 age cohorts of mRNA vaccine recipients. We have further measured neutralizing antibody titers for B.1.617.1 (Kappa) and B.1.595; a SARS-CoV-2 isolate bearing Spike mutation E484Q. As reported, robust immunity required the second dose of vaccine. Older vaccinees manifested robust cellular immunity against early-pandemic SARS-CoV-2 and more recent variants, which remained statistically comparable to the adult group. The older cohort had lower neutralizing capacity at the first time point following the second dose, but at later time points immunity was indistinguishable between them. While the duration of these immune responses remains to be determined over longer periods of time, these results provide reasons for optimism regarding vaccine protection of older adults against SARS-CoV-2 variants and inform thinking about boost vaccination with variant vaccines. eTOC summaryVaccine responses are often diminished with aging, but we found strong responses to SARS-CoV-2 in older adults following mRNA vaccination. T cell responses were not diminished when confronted by SARS-CoV-2 variants. Neutralizing Ab were reduced but not more than those in adults. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=73 SRC="FIGDIR/small/453287v2_ufig1.gif" ALT="Figure 1"> View larger version (16K): org.highwire.dtl.DTLVardef@1091655org.highwire.dtl.DTLVardef@1996173org.highwire.dtl.DTLVardef@ccf2f9org.highwire.dtl.DTLVardef@163ed22_HPS_FORMAT_FIGEXP M_FIG C_FIG Created with BioRender.com

immunology↗

bioRxiv2019

MAVS regulates the quality of the antibody response to West-Nile Virus

A key difference that distinguishes viral infections from protein immunizations is the recognition of viral nucleic acids by cytosolic pattern recognition receptors (PRRs) such as RNA-sensing Rig-I-like receptors (RLRs). Insights into the specific functions of cytosolic PRRs in the instruction of adaptive immunity are therefore critical for the understanding of protective immunity to infections. West Nile virus (WNV) infection of mice deficent of MAVS, the essential RLR signaling adaptor, results in a defective adaptive immune response. While this finding suggests a role for RLRs in the instruction of adaptive immunity to WNV, it is difficult to interpret due to the high WNV viremia, associated exessive antigen loads, and pathology in the absence of a MAVS-dependent innate immune response. To overcome these limitations, we have infected MAVS-deficient mice with a single-round-of-infection mutant of WNV called RepliVAX (RWN). RWN-infected MAVS-deficient (MAVSKO) mice failed to produce an effective neutralizing antibody response to WNV despite normal titers of antibodies targeting the viral WNV-E protein. This defect occurred indepedently of antigen loads or overt pathology. The specificity of the antibody response in RWN-infected MAVSKO mice remained unchanged and was still dominated by antibodies that bound the neutralizing lateral ridge (LR) epitope in the DIII domain of WNV-E. Instead, MAVSKO mice produced IgM antibodies, the dominant isotype controlling primary WNV infection, with lower affinity for the DIII domain. Our findings suggest that RLR-dependent signals are important for the quality of the humoral immune response to WNV.

immunology↗