Biology subjects

Nikolich, J. Z.

Publications and source records attributed to Nikolich, J. Z..

3 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↗

bioRxiv2022

T-cell cellular stress and reticulocyte signatures, but not loss of naive T lymphocytes, characterize severe COVID-19 in older adults

In children and younger adults up to 39 years of age, SARS-CoV-2 usually elicits mild symptoms that resemble the common cold. Disease severity increases with age starting at 30 and reaches astounding mortality rates that are ~330 fold higher in persons above 85 years of age compared to those 18-39 years old. To understand age-specific immune pathobiology of COVID-19 we have analyzed soluble mediators, cellular phenotypes, and transcriptome from over 80 COVID-19 patients of varying ages and disease severity, carefully controlling for age as a variable. We found that reticulocyte numbers and peripheral blood transcriptional signatures robustly correlated with disease severity. By contrast, decreased numbers and proportion of naive T-cells, reported previously as a COVID-19 severity risk factor, were found to be general features of aging and not of COVID-19 severity, as they readily occurred in older participants experiencing only mild or no disease at all. Single-cell transcriptional signatures across age and severity groups showed that severe but not moderate/mild COVID-19 causes cell stress response in different T-cell populations, and some of that stress was unique to old severe participants, suggesting that in severe disease of older adults, these defenders of the organism may be disabled from performing immune protection. These findings shed new light on interactions between age and disease severity in COVID-19.

immunology↗