# Mechanism of Immune Dysfunction and Morbid Outcomes in Response to Shock/Sepsis

> **NIH NIH R35** · RHODE ISLAND HOSPITAL · 2022 · $77,639

## Abstract

PROJECT SUMMARY/ABSTRACT
At last count, sepsis was reported to be the leading cause of death in U.S hospital intensive care units (ICU);
accounting for ~1 in 5 deaths world-wide; its incidence is anticipated to rise as the populations in developed
countries age; and it was the consensus cause of death assigned to those dying from COVID-19 infection.
Most frustrating, is that while we continue to optimize the supportive care for these critically ill patients, we have
yet to see a novel molecular etiology-based therapy make a sustained impact on overall septic morbidity/
mortality. Excitingly, while working for years on defining numerous defects of components of both adaptive and
innate immune responsiveness induced by shock and/or sepsis, we have uncovered novel role(s) for a number
of the B7-family of cell-associated co-inhibitory receptors, Programmed Cell Death Receptor-1 [PD-1], B-/T
Lymphocyte Attenuator [BTLA], recently, V-domain Immunoglobulin Suppressor of T cell Activation [VISTA,
a.k.a., B7-H5, PD-1H] and their respective cell surface ligands; popularly referred to as checkpoint proteins. In
this competitive renewal of our MIRA program, we propose to continue to push forward the 3 project areas we
brought together previously under the over-arching concept that by understanding the mechanism(s) of
injury/shock and/or sepsis that serve to predispose animals (experimentally) or critically ill/injured
patients to develop morbid outcomes, we can elucidate not only novel prognostic markers of patient’s
course but uncover unique therapeutic targets for their treatment. In the 1st Project area, we will
determine how the select expression of PD-1, BTLA or VISTA, on myeloid as opposed to lymphoid cells alters
the development of morbid events associated with sepsis; then, how the expression of ligands for these co-
inhibitory molecules, on leukocytes and/or endothelial/epithelial cells, contribute to the onset of septic liver,
intestine and/or kidney dysfunction. In our 2nd Project area, we will utilize a novel murine model of indirect-
acute lung injury (iALI)(dual insults of hemorrhage shock followed by cecal ligation & puncture [CLP]) to ask
how checkpoint protein expression not only effect the patho-mechanisms driving the development of iALI, but
how are these co-inhibitors alter cell ‘priming’/’innate immune memory’/function by following pulmonary
immune/non-immune cell transcriptomic/ epigenomic fate/programing. Finally, (3rd Project) since the neonate
possesses a unique/naïve immune system and is more susceptible to morbid response in the face of infectious
challenge; we ask how the expression of members of the B-7 family of proteins and/or their ligands not only
have a comparative impact on the response to septic insult, but how this alters their microbiota and epigenetic
makeup/immune function as survivors mature? To do this we will interrogate these 3 cogent models of sepsis,
shock/sepsis and/or neonatal sepsis, by applying a combination ...

## Key facts

- **NIH application ID:** 10596391
- **Project number:** 3R35GM118097-07S1
- **Recipient organization:** RHODE ISLAND HOSPITAL
- **Principal Investigator:** Alfred Ayala
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $77,639
- **Award type:** 3
- **Project period:** 2016-05-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10596391

## Citation

> US National Institutes of Health, RePORTER application 10596391, Mechanism of Immune Dysfunction and Morbid Outcomes in Response to Shock/Sepsis (3R35GM118097-07S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10596391. Licensed CC0.

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