Patricia A. Sheridan

Bio: Patricia A. Sheridan is an academic researcher from University of North Carolina at Chapel Hill. The author has contributed to research in topics: Immune system & CD8. The author has an hindex of 17, co-authored 26 publications receiving 1831 citations. Previous affiliations of Patricia A. Sheridan include University of Rochester.

Obesity is associated with impaired immune response to influenza vaccination in humans

Abstract: Obesity is an independent risk factor for morbidity and mortality from pandemic influenza H1N1. Influenza is a significant public health threat, killing an estimated 250 000–500 000 people worldwide each year. More than one in ten of the world's adult population is obese and more than two-thirds of the US adult population is overweight or obese. No studies have compared humoral or cellular immune responses to influenza vaccination in healthy weight, overweight and obese populations despite clear public health importance. The study employed a convenience sample to determine the antibody response to the 2009–2010 inactivated trivalent influenza vaccine (TIV) in healthy weight, overweight and obese participants at 1 and 12 months post vaccination. In addition, activation of CD8+ T cells and expression of interferon-γ and granzyme B were measured in influenza-stimulated peripheral blood mononuclear cell (PBMC) cultures. Body mass index (BMI) correlated positively with higher initial fold increase in IgG antibodies detected by enzyme-linked immunosorbent assay to TIV, confirmed by HAI antibody in a subset study. However, 12 months post vaccination, higher BMI was associated with a greater decline in influenza antibody titers. PBMCs challenged ex vivo with vaccine strain virus, demonstrated that obese individuals had decreased CD8+ T-cell activation and decreased expression of functional proteins compared with healthy weight individuals. These results suggest obesity may impair the ability to mount a protective immune response to influenza virus.

Diet-Induced Obese Mice Have Increased Mortality and Altered Immune Responses When Infected with Influenza Virus

Abstract: Obesity is associated with an impaired immune response, an increased susceptibility to bacterial infection, and a chronic increase in proinflammatory cytokines such as IL-6 and TNFalpha. However, few studies have examined the effect of obesity on the immune response to viral infections. Because infection with influenza is a leading cause of morbidity and mortality worldwide, we investigated the effect of obesity on early immune responses to influenza virus exposure. Diet-induced obese and lean control C57BL/6 mice were infected with influenza A/PR8/34, and lung pathology and immune responses were examined at d 0 (uninfected), 3, and 6, postinfection. Following infection, diet-induced obese mice had a significantly higher mortality rate than the lean controls and elevated lung pathology. Antiviral and proinflammatory cytokine mRNA production in the lungs of the infected mice was markedly different between obese and lean mice. IFNalpha and beta were only minimally expressed in the infected lungs of obese mice and there was a notable delay in expression of the proinflammatory cytokines IL-6 and TNFalpha. Additionally, obese mice had a substantial reduction in NK cell cytotoxicity. These data indicate that obesity inhibits the ability of the immune system to appropriately respond to influenza infection and suggests that obesity may lead to increased morbidity and mortality from viral infections.

Diet-induced obesity impairs the T cell memory response to influenza virus infection.

Abstract: The Centers for Disease Control and Prevention has suggested that obesity may be an independent risk factor for increased severity of illness from the H1N1 pandemic strain. Memory T cells generated during primary influenza infection target internal proteins common among influenza viruses, making them effective against encounters with heterologous strains. In male, diet-induced obese C57BL/6 mice, a secondary H1N1 influenza challenge following a primary H3N2 infection led to a 25% mortality rate (with no loss of lean controls), 25% increase in lung pathology, failure to regain weight, and 10- to 100-fold higher lung viral titers. Furthermore, mRNA expression for IFN-gamma was >60% less in lungs of obese mice, along with one third the number of influenza-specific CD8(+) T cells producing IFN-gamma postsecondary infection versus lean controls. Memory CD8(+) T cells from obese mice had a >50% reduction in IFN-gamma production when stimulated with influenza-pulsed dendritic cells from lean mice. Thus, the function of influenza-specific memory T cells is significantly reduced and ineffective in lungs of obese mice. The reality of a worldwide obesity epidemic combined with yearly influenza outbreaks and the current pandemic makes it imperative to understand how influenza virus infection behaves differently in an obese host. Moreover, impairment of memory responses has significant implications for vaccine efficacy in an obese population.

Overweight and obese adult humans have a defective cellular immune response to pandemic H1N1 Influenza a virus

Abstract: Objective Obese adults have a greater risk of morbidity and mortality from infection with pandemic H1N1 influenza A virus (pH1N1). The objective of the present study was to elucidate the specific mechanisms by which obesity and overweight impact the cellular immune response to pH1N1. Design and Methods Peripheral blood mononuclear cells from healthy weight, overweight, and obese individuals were stimulated ex vivo with live pH1N1 and then markers of activation and function were measured using flow cytometry and cytokine secretion was measured using cytometric bead array assays. Results CD4+ and CD8+ T cells from overweight and obese individuals expressed lower levels of CD69, CD28, CD40 ligand, and interleukin-12 receptor, as well as, produced lower levels of interferon-γ and granzyme B, compared with healthy weight individuals, suggesting deficiencies in activation and function are indicated. Dendritic cells from the three groups expressed similar levels of major histocompatibility complex-II, CD40, CD80, and CD86, as well as, produced similar levels of interleukin-12. Conclusions The defects in CD4+ and CD8+ T cells may contribute to the increased morbidity and mortality from pH1N1 in obese individuals. These data also provide evidence that both overweight and obesity cause impairments in immune function.

Selective impairment in dendritic cell function and altered antigen-specific CD8+ T-cell responses in diet-induced obese mice infected with influenza virus.

Abstract: There is a clear link between obesity and metabolic disorders; however, little is known about the effect of obesity on immune function, particularly during an infection. We have previously reported that diet-induced obese mice are more susceptible to morbidity and mortality during influenza infection than lean mice. Obese mice displayed aberrant innate immune responses characterized by minimal induction of interferon (IFN)-alpha/beta, delayed expression of pro-inflammatory cytokines and chemokines, and impaired natural killer cell cytotoxicity. To further examine the abnormal immune response of diet-induced obese mice, we analysed the cellularity of their lungs during influenza virus infection. We found delayed mononuclear cell entry with a marked decrease in dendritic cells (DCs) throughout the infection. Given the critical role of the DC in activating the cell-mediated immune response, we also analysed the functional capacity of DCs from obese mice. We found that, while obesity did not interfere with antigen uptake and migration, it did impair DC antigen presentation. This was probably attributable to an altered cytokine milieu, as interleukin (IL)-2, IL-12, and IL-6 were differentially regulated in the obese mice. Overall, this did not impact the total number of virus-specific CD8(+) T cells that were elicited, but did affect the number and frequency of CD3(+) and CD8(+) T cells in the lung. Thus, obesity interferes with cellular responses during influenza infection, leading to alterations in the T-cell population that ultimately may be detrimental to the host.

A lineage of myeloid cells independent of Myb and hematopoietic stem cells

Abstract: Macrophage Development Rewritten Macrophages provide protection against a wide variety of infections and critically shape the inflammatory environment in many tissues. These cells come in many flavors, as determined by differences in gene expression, cell surface phenotype and specific function. Schulz et al. (p. 86, published online 22 March) investigated whether adult macrophages all share a common developmental origin. Immune cells, including most macrophages, are widely thought to arise from hematopoietic stem cells (HSCs), which require the transcription factor Myb for their development. Analysis of Myb-deficient mice revealed that a population of yolk-sac–derived, tissue-resident macrophages was able to develop and persist in adult mice in the absence of HSCs. Importantly, yolk sac–derived macrophages also contributed substantially to the tissue macrophage pool even when HSCs were present. In mice, a population of tissue-resident macrophages arises independently of bone marrow–derived stem cells. Macrophages and dendritic cells (DCs) are key components of cellular immunity and are thought to originate and renew from hematopoietic stem cells (HSCs). However, some macrophages develop in the embryo before the appearance of definitive HSCs. We thus reinvestigated macrophage development. We found that the transcription factor Myb was required for development of HSCs and all CD11bhigh monocytes and macrophages, but was dispensable for yolk sac (YS) macrophages and for the development of YS-derived F4/80bright macrophages in several tissues, such as liver Kupffer cells, epidermal Langerhans cells, and microglia—cell populations that all can persist in adult mice independently of HSCs. These results define a lineage of tissue macrophages that derive from the YS and are genetically distinct from HSC progeny.

Prevention and Control of Seasonal Influenza with Vaccines: Recommendations of the Advisory Committee on Immunization Practices - United States, 2020-21 Influenza Season.

Abstract: This report updates the 2020-21 recommendations of the Advisory Committee on Immunization Practices (ACIP) regarding the use of seasonal influenza vaccines in the United States (MMWR Recomm Rep 2020;69[No. RR-8]). Routine annual influenza vaccination is recommended for all persons aged ≥6 months who do not have contraindications. For each recipient, a licensed and age-appropriate vaccine should be used. ACIP makes no preferential recommendation for a specific vaccine when more than one licensed, recommended, and age-appropriate vaccine is available. During the 2021-22 influenza season, the following types of vaccines are expected to be available: inactivated influenza vaccines (IIV4s), recombinant influenza vaccine (RIV4), and live attenuated influenza vaccine (LAIV4).The 2021-22 influenza season is expected to coincide with continued circulation of SARS-CoV-2, the virus that causes COVID-19. Influenza vaccination of persons aged ≥6 months to reduce prevalence of illness caused by influenza will reduce symptoms that might be confused with those of COVID-19. Prevention of and reduction in the severity of influenza illness and reduction of outpatient visits, hospitalizations, and intensive care unit admissions through influenza vaccination also could alleviate stress on the U.S. health care system. Guidance for vaccine planning during the pandemic is available at https://www.cdc.gov/vaccines/pandemic-guidance/index.html. Recommendations for the use of COVID-19 vaccines are available at https://www.cdc.gov/vaccines/hcp/acip-recs/vacc-specific/covid-19.html, and additional clinical guidance is available at https://www.cdc.gov/vaccines/covid-19/clinical-considerations/covid-19-vaccines-us.html.Updates described in this report reflect discussions during public meetings of ACIP that were held on October 28, 2020; February 25, 2021; and June 24, 2021. Primary updates to this report include the following six items. First, all seasonal influenza vaccines available in the United States for the 2021-22 season are expected to be quadrivalent. Second, the composition of 2021-22 U.S. influenza vaccines includes updates to the influenza A(H1N1)pdm09 and influenza A(H3N2) components. U.S.-licensed influenza vaccines will contain hemagglutinin derived from an influenza A/Victoria/2570/2019 (H1N1)pdm09-like virus (for egg-based vaccines) or an influenza A/Wisconsin/588/2019 (H1N1)pdm09-like virus (for cell culture-based and recombinant vaccines), an influenza A/Cambodia/e0826360/2020 (H3N2)-like virus, an influenza B/Washington/02/2019 (Victoria lineage)-like virus, and an influenza B/Phuket/3073/2013 (Yamagata lineage)-like virus. Third, the approved age indication for the cell culture-based inactivated influenza vaccine, Flucelvax Quadrivalent (ccIIV4), has been expanded from ages ≥4 years to ages ≥2 years. Fourth, discussion of administration of influenza vaccines with other vaccines includes considerations for coadministration of influenza vaccines and COVID-19 vaccines. Providers should also consult current ACIP COVID-19 vaccine recommendations and CDC guidance concerning coadministration of these vaccines with influenza vaccines. Vaccines that are given at the same time should be administered in separate anatomic sites. Fifth, guidance concerning timing of influenza vaccination now states that vaccination soon after vaccine becomes available can be considered for pregnant women in the third trimester. As previously recommended, children who need 2 doses (children aged 6 months through 8 years who have never received influenza vaccine or who have not previously received a lifetime total of ≥2 doses) should receive their first dose as soon as possible after vaccine becomes available to allow the second dose (which must be administered ≥4 weeks later) to be received by the end of October. For nonpregnant adults, vaccination in July and August should be avoided unless there is concern that later vaccination might not be possible. Sixth, contraindications and precautions to the use of ccIIV4 and RIV4 have been modified, specifically with regard to persons with a history of severe allergic reaction (e.g., anaphylaxis) to an influenza vaccine. A history of a severe allergic reaction to a previous dose of any egg-based IIV, LAIV, or RIV of any valency is a precaution to use of ccIIV4. A history of a severe allergic reaction to a previous dose of any egg-based IIV, ccIIV, or LAIV of any valency is a precaution to use of RIV4. Use of ccIIV4 and RIV4 in such instances should occur in an inpatient or outpatient medical setting under supervision of a provider who can recognize and manage a severe allergic reaction; providers can also consider consulting with an allergist to help identify the vaccine component responsible for the reaction. For ccIIV4, history of a severe allergic reaction (e.g., anaphylaxis) to any ccIIV of any valency or any component of ccIIV4 is a contraindication to future use of ccIIV4. For RIV4, history of a severe allergic reaction (e.g., anaphylaxis) to any RIV of any valency or any component of RIV4 is a contraindication to future use of RIV4. This report focuses on recommendations for the use of vaccines for the prevention and control of seasonal influenza during the 2021-22 influenza season in the United States. A brief summary of the recommendations and a link to the most recent Background Document containing additional information are available at https://www.cdc.gov/vaccines/hcp/acip-recs/vacc-specific/flu.html. These recommendations apply to U.S.-licensed influenza vaccines used according to Food and Drug Administration-licensed indications. Updates and other information are available from CDC's influenza website (https://www.cdc.gov/flu); vaccination and health care providers should check this site periodically for additional information.

Selenium in human health and disease.

Abstract: This review covers current knowledge of selenium in the environment, dietary intakes, metabolism and status, functions in the body, thyroid hormone metabolism, antioxidant defense systems and oxidative metabolism, and the immune system. Selenium toxicity and links between deficiency and Keshan disease and Kashin-Beck disease are described. The relationships between selenium intake/status and various health outcomes, in particular gastrointestinal and prostate cancer, cardiovascular disease, diabetes, and male fertility, are reviewed, and recent developments in genetics of selenoproteins are outlined. The rationale behind current dietary reference intakes of selenium is explained, and examples of differences between countries and/or expert bodies are given. Throughout the review, gaps in knowledge and research requirements are identified. More research is needed to improve our understanding of selenium metabolism and requirements for optimal health. Functions of the majority of the selenoproteins await characterization, the mechanism of absorption has yet to be identified, measures of status need to be developed, and effects of genotype on metabolism require further investigation. The relationships between selenium intake/status and health, or risk of disease, are complex but require elucidation to inform clinical practice, to refine dietary recommendations, and to develop effective public health policies.