Research
Our ability to fight infection and maintain tissue homeostasis relies heavily on a tightly regulated and well-orchestrated immune response to microbes both commensal and pathogenic as well as responding to signals of cellular damage.
The Messaoudi lab investigates how various factors ranging from age to substance use disorder and infection dysregulate the cellular and molecular mechanisms that regulate immune responses. To achieve this goal, we use a range of techniques to interrogate function of various immune cells.
Dysregulation of immunity by substance use disorder
Substance use disorders dysregulate the immune system leading to heightened inflammation and reduced antimicrobial responses, but the exact mechanisms are not fully understood. Over the last decade, we have leveraged a macaque model of voluntary ethanol self-administration developed by our long-term collaborator Dr. Kathy Grant (Oregon National Primate Research Center) to uncover how chronic heavy drinking disrupts immune homeostasis. We have also initiated additional studies examining the impact of stimulants, opioids, and cannabis on immune fitness.
Role of the microbiome in health and disease
It is well established that the microbiome plays a critical role in the maturation of the immune system as well as modulate susceptibility to infection and development and/or exacerbation of other chronic diseases. Using both 16s rRNA sequencing and shotgun metagenomics, we have investigated the relationship between the infant microbiome and susceptibility to enteric disease as well as shifts in microbial communities with age and pregnancy.
Mechanisms of viral pathogenesis and vaccination strategies
Viral diseases continue to pose a significant threat to human health. Viruses can both subvert the host immune response as well as usurp immune cells to disseminate. A better understanding of the molecular mechanisms of immune subversion and manipulation by viruses will pave the way for new antivirals and vaccines. Our laboratory has investigated the mechanisms of virulence of varicella zoster virus (VZV), yellow fever (YFV), Ebola (EBOV), H1N1 influenza, Chikungunya (CHIKV), and SARS-CoV-2 by developing animal models, characterizing changes in host gene expression, and testing the immunogenicity and efficacy of novel vaccine platforms using systems biology approaches.
Aging and immunity
Aging is accompanied by a dysregulation in the immune system generally referred to as immune senescence that increases susceptibility to infection and delays wound healing. Early work from our group showed that these functional changes are accompanied by the appearance of T and B cell clonal expansions that constrict T and B cell repertoire diversity and interfere with the immune response to infection. Our laboratory has also investigated the impact of age-related decline/loss of sex steroids (menopause/andropause) on immune senescence and showed that menopause reduced immune response to vaccination and that estradiol treatment can partially rescue this loss. Similarly, short-term androgen supplementation improves some but not all aspects of immune senescence in aged male macaques. Ongoing efforts are now aimed at uncovering age-related defects in host defense to microbial infections (VZV and non-tuberculous mycobacteria).
Immunity at the maternal-fetal interface
Pregnancy is characterized by significant immunological shifts both in circulation and within the placenta that are critical for implantation, fetal tolerance and growth, and ultimately parturition. Disruptions in this tightly controlled immune clock of pregnancy by environmental and infectious agents can lead to adverse long-term health effects for both mother and offspring. Studies in our laboratory aim to uncover the impact of maternal infection, obesity, as well as substance use disorder on the placental, maternal, and neonatal immune systems.
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