Biology subjects

Aboellail, T.

Publications and source records attributed to Aboellail, T..

4 recordsLinked to original sources

bioRxiv2025

Biological Sex Differences after High and Low Doses of Influenza A Virus Infection in a Diet-induced Obesity Mouse Model

Obesity is an independent risk factor for influenza A virus (IAV) pathogenesis. In non-obese hosts, following IAV infection, adult females develop more severe disease than males. Limited research on biological sex differences following IAV infection in individuals with obesity forms the basis for this study. Male and female C57BL/6J mice were treated with high-fat or low-fat diets to obtain mice with or without obesity. They were inoculated intranasally with a high (103) or low dose (101.5 TCID50) of mouse-adapted A/California/04/2009 H1N1 IAV and followed for 21 days post-infection (dpi) for morbidity. Subsets of mice were euthanized at different dpi to measure lung virus titers, histopathological changes, cellular infiltration, and cytokine induction. After a high-dose infection, females with obesity demonstrated shorter median survival time, greater parenchymal inflammation, and heightened induction of inflammatory markers than males with obesity. After a low-dose infection, females than males, and mice with obesity than the non-obese mice, exhibited severe morbidity. Female mice with obesity exhibited the greatest disease severity, where 25% (2/8) reached humane endpoint. Delayed but persistent inflammatory changes were observed in females with obesity, characterized by relatively lower pathological changes, lesser induction of cytokines and chemokines, and reduced myeloid and lymphoid infiltration in the lungs at 3 dpi followed by sustained pathological changes and cytokine and chemokine induction at 21 dpi. Our study suggests that the biological sex difference following IAV infection persists during obesity. Females with obesity experience greater influenza disease severity than males, possibly driven by more severe dysregulation of inflammatory responses. ImportanceThe prevalence of obesity is increasing worldwide. The risk of developing severe disease following influenza virus infection is higher in individuals with obesity. Males and females with obesity differ in terms of fat deposition and inflammatory and metabolic biomarkers. These differences can alter the outcomes of influenza-induced disease pathogenesis. The observation of sex differences in IAV pathogenesis among non-obese hosts underscores the importance of determining whether similar differences occur in the context of obesity. Indeed, our study suggested that females with obesity experience greater disease severity than males with obesity after IAV infection. Understanding the immunological mechanisms of such differences will advance precision medicine approaches to develop safer and more effective preventive and therapeutic strategies against influenza for the high-risk populations with obesity.

immunology↗

bioRxiv2025

Females with Obesity Exhibit Greater Influenza Vaccine-induced Immunity and Protection than Males in a Mouse Model

IntroductionObesity is increasing globally, and it negatively impacts influenza vaccine efficacy. Although sex differences in influenza vaccine responses are studied in non-obese hosts, studies investigating sex differences in influenza vaccine-induced immunity and protection during obesity are limited. Materials and methodsUsing the C57BL/6J mouse model of high-fat diet (HFD)-induced obesity or low-fat diet controls, we investigated sex differences in influenza vaccine-induced immunity and protection during obesity. Male and female mice with or without obesity were vaccinated intramuscularly twice at a 3-week interval with an inactivated 2009 H1N1 influenza A virus (IAV) vaccine. At 35 days post-vaccination (dpv), antibody responses in plasma and B- and T-cell responses in spleen and bone marrow were quantified. At 42 dpv, mice were intranasally challenged with a drift variant of the H1N1 IAV, and disease severity was assessed by monitoring the change in body mass up to 21 days post-challenge (dpc). Subsets of mice were euthanized at 3 dpc to determine pulmonary virus replication (TCID50 assay), histopathology (H&E staining), and cytokine/chemokine responses (multiplex ELISA). ResultsFemale mice, irrespective of diet and obesity status, developed higher antibody responses and were better protected compared to males. Vaccinated males with obesity mounted the poorest antibody responses, experienced a more severe disease, were unable to clear replicating virus from the lungs effectively, and demonstrated heightened pulmonary inflammation. Despite these differences, splenic B- and T-cell frequencies were comparable, suggesting the inefficiency of B cells to produce antibodies in males but not in females with obesity. DiscussionOur findings suggest that sex differences is observed in influenza vaccine-induced immunity and protection during obesity, where males are more severely affected. These findings highlight the importance of considering biological sex and obesity status in influenza vaccine design and testing.

immunology↗

bioRxiv2023

Regulatory T Cell-like Response to SARS-CoV-2 in Jamaican Fruit Bats Transduced with Human ACE2

Insectivorous Old World horseshoe bats (Rhinolophus spp.) are the likely source of the ancestral SARS-CoV-2 prior to its spillover into humans and causing the COVID-19 pandemic. Natural coronavirus infections of bats appear to be principally confined to the intestines, suggesting fecal-oral transmission; however, little is known about the biology of SARS-related coronaviruses in bats. Previous experimental challenges of Egyptian fruit bats (Rousettus aegyptiacus) resulted in limited infection restricted to the respiratory tract, whereas insectivorous North American big brown bats (Eptesicus fuscus) showed no evidence of infection. In the present study, we challenged Jamaican fruit bats (Artibeus jamaicensis) with SARS-CoV-2 to determine their susceptibility. Infection was confined to the intestine for only a few days with prominent viral nucleocapsid antigen in epithelial cells, and mononuclear cells of the lamina propria and Peyers patches, but with no evidence of infection of other tissues; none of the bats showed visible signs of disease or seroconverted. Expression levels of ACE2 were low in the lungs, which may account for the lack of pulmonary infection. Bats were then intranasally inoculated with a replication-defective adenovirus encoding human ACE2 and 5 days later challenged with SARS-CoV-2. Viral antigen was prominent in lungs for up to 14 days, with loss of pulmonary cellularity during this time; however, the bats did not exhibit weight loss or visible signs of disease. From day 7, bats had low to moderate IgG antibody titers to spike protein by ELISA, and one bat on day 10 had low-titer neutralizing antibodies. CD4+ helper T cells became activated upon ex vivo recall stimulation with SARS-CoV-2 nucleocapsid peptide library and exhibited elevated mRNA expression of the regulatory T cell cytokines interleukin-10 and transforming growth factor-{beta}, which may have limited inflammatory pathology. Collectively, these data show that Jamaican fruit bats are poorly susceptibility to SARS-CoV-2 but that expression of human ACE2 in their lungs leads to robust infection and an adaptive immune response with low-titer antibodies and a regulatory T cell-like response that may explain the lack of prominent inflammation in the lungs. This model will allow for insight of how SARS-CoV-2 infects bats and how bat innate and adaptive immune responses engage the virus without overt clinical disease. Author SummaryBats are reservoir hosts of many viruses that infect humans, yet little is known about how they host these viruses, principally because of a lack of relevant and susceptible bat experimental infection models. Although SARS-CoV-2 originated in bats, no robust infection models of bats have been established. We determined that Jamaican fruit bats are poorly susceptible to SARS-CoV-2; however, their lungs can be transduced with human ACE2, which renders them susceptible to SARS-CoV-2. Despite robust infection of the lungs and diminishment of pulmonary cellularity, the bats showed no overt signs of disease and cleared the infection after two weeks. Despite clearance of infection, only low-titer antibody responses occurred and only a single bat made neutralizing antibody. Assessment of the CD4+ helper T cell response showed that activated cells expressed the regulatory T cell cytokines IL-10 and TGF{beta} that may have tempered pulmonary inflammation.

microbiology↗

bioRxiv2020

SARS-CoV-2 infection, neuropathogenesis and transmission among deer mice: Implications for reverse zoonosis to New World rodents

Coronavirus disease-19 (COVID-19) emerged in November, 2019 in China and rapidly became pandemic. As with other coronaviruses, a preponderance of evidence suggests the virus originated in horseshoe bats (Rhinolophus spp.) and likely underwent a recombination event in an intermediate host prior to entry into human populations. A significant concern is that SARS-CoV-2 could become established in secondary reservoir hosts outside of Asia. To assess this potential, we challenged deer mice (Peromyscus maniculatus) with SARS-CoV-2 and found robust virus replication in the upper respiratory tract, lungs and intestines, with detectable viral RNA for up to 21 days in oral swabs and 14 days in lungs. Virus entry into the brain also occurred, likely via gustatory-olfactory-trigeminal pathway with eventual compromise to the blood brain barrier. Despite this, no conspicuous signs of disease were observed and no deer mice succumbed to infection. Expression of several innate immune response genes were elevated in the lungs, notably IFN, Cxcl10, Oas2, Tbk1 and Pycard. Elevated CD4 and CD8{beta} expression in the lungs was concomitant with Tbx21, IFN{gamma} and IL-21 expression, suggesting a type I inflammatory immune response. Contact transmission occurred from infected to naive deer mice through two passages, showing sustained natural transmission. In the second deer mouse passage, an insertion of 4 amino acids occurred to fixation in the N-terminal domain of the spike protein that is predicted to form a solvent-accessible loop. Subsequent examination of the source virus from BEI Resources indicated the mutation was present at very low levels, demonstrating potent purifying selection for the insert during in vivo passage. Collectively, this work has determined that deer mice are a suitable animal model for the study of SARS-CoV-2 pathogenesis, and that they have the potential to serve as secondary reservoir hosts that could lead to periodic outbreaks of COVID-19 in North America.

microbiology↗