Biology subjects

Griffith, T. S.

Publications and source records attributed to Griffith, T. S..

3 recordsLinked to original sources

bioRxiv2023

Hepatic IRE1 Protects Against Septic Cardiac Failure

SUMMARYMetabolic reprogramming in response to infection plays a critical role for septic survival. During a septic episode, the heart heavily relies on hepatic lipid particles to prevent heart damage and failure. Inositol- Requiring Enzyme 1 (IRE1) is the most conserved unfolded protein response (UPR) regulator that governs homeostasis of the endoplasmic reticulum (ER), the major site for lipid synthesis and processing. Here we show that hepatocyte IRE1 is indispensable for protecting against septic mortality in two different rodent models of experimental sepsis. The protective effect of hepatic IRE1 was not attributed to the inflammatory response since hepatic IRE1 deletion did not alter hepatic or systemic cytokine response. However, loss of IRE1 in the liver significantly augmented septic cardiac dysfunction in part due to a skewed immune-metabolic balance. Lipidomic and metabolomic analyses further revealed that loss of IRE1 in the liver compromised adaptive intrahepatic and circulating lipid reprogramming, including VLDL, in response to septic challenge. Furthermore, we identified that the protective effects against septic mortality are mediated by a non-canonical IRE1-dependent mechanism. Together, our study provides the first insight into how a disruption of hepatic ER-mediated lipid metabolic regulation promotes sepsis-associated cardiac immuno-metabolic imbalance.

pathology↗

bioRxiv2023

A subset of CD4+ effector memory T cells limit immunity to pulmonary viral infection and prevent tissue pathology via activation of latent TGFβ

A rapid immune response to pathogen re-exposure underpins immunological memory, with protection against divergent pathogens such as heterologous or novel viral strains requiring cross-reactive memory T cells. Understanding the pathways that control memory T cell function is therefore important for the rational design of viral vaccines and will aid the discovery of therapies to boost anti-viral immunity. Here, we identify a sub-population of memory T cells that limit secondary immune responses to viral re-infection, which is crucial in preventing host tissue damage. We show that a population of CD4+ effector memory T (TEM) cells activate the important immunoregulatory cytokine TGF{beta}, via expression of an integrin, v{beta}8. Integrin v{beta}8 expression marks a transcriptionally distinct sub-population of CD4+ TEM, enriched for anti-inflammatory pathways. Loss of integrin v{beta}8 on murine CD4+ TEM, but not Foxp3+ regulatory T cells (TREG), led to exacerbated virus-specific CD8+ T cell responses following secondary influenza A virus (IAV) infection, which was associated with enhanced viral clearance. However, although accelerating clearance, loss of integrin v{beta}8 expression on CD4+ TEM resulted in enhanced lung pathology following secondary IAV infection, which was completely reversed by adoptive transfer of v{beta}8+ CD4+ TEM cells. These data highlight a new pathway by which a distinct CD4+ memory T cell subset restrains anti-viral immunity to prevent host tissue damage during secondary viral infection. Such pathways could be targeted therapeutically to either boost memory T-cell-mediated immunity or restrain host tissue damage during viral infection.

immunology↗

bioRxiv2021

Autoimmunity increases susceptibility to and mortality from sepsis

Our prior publication detailing how sepsis influences subsequent development of EAE presented a conceptual advance in understanding the post-sepsis chronic immunoparalysis state (Jensen et al., 2020). However, the reverse scenario (autoimmunity prior to sepsis) defines a high-risk patient population whose susceptibility to sepsis remains poorly defined. Herein, we present a retrospective analysis of University of Iowa Hospital and Clinics patients demonstrating increased sepsis incidence among MS, relative to non-MS, patients. To interrogate how autoimmune disease influences host susceptibility to sepsis well-established murine models of MS and sepsis, EAE and CLP, respectively, were utilized. EAE, relative to non-EAE, mice were highly susceptible to sepsis-induced mortality with elevated cytokine storms. These results were further recapitulated in LPS and S. pneumoniae sepsis models. This work highlights both the relevance of identifying highly susceptible patient populations and expands the growing body of literature that host immune status at the time of septic insult is a potent mortality determinant.

immunology↗