# Characterizing Macrophages as "Hide-Outs" for Chronic Pathogens

> **NIH NIH DP2** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2022 · $502,500

## Abstract

PROJECT SUMMARY
This proposal describes the framework of an NIAID New Innovators DP2 award for Kiera Clayton, PhD. Dr.
Clayton is currently a postdoctoral fellow under the supervision of Dr. Bruce Walker at the Ragon Institute of
MGH, MIT and Harvard, whose current research focuses on T cell and NK cell-mediated killing of HIV-infected
macrophages, and the implications for HIV reservoir persistence and macrophage-mediated inflammation. In
addition to Dr. Clayton’s published work suggesting that macrophages are resistant to T cell-mediated killing,
preliminary results included in this proposal suggest that HIV exploits macrophages to evade NK cell-mediated
killing, by mechanisms distinct from those used to evade T cell responses. As macrophages also act as the
primary cellular reservoir for other chronic pathogens, including Mycobacterium tuberculosis (Mtb), the question
remains whether macrophages provide a common “Hide-Out” for immunoevasion. Thus, the overall goal of this
proposal is to characterize the mechanisms employed by macrophages infected by different chronic pathogens
to evade immune-mediated clearance and explore the possibility of targeting a common immunoevasion
pathway to enhance T cell and NK cell killing of infected macrophages. This proposal focuses on three Research
Areas. The first Research Area will build on preliminary data to define the mechanisms by which HIV-infected
macrophages prevent NK cell-mediated killing. To quantify the resistance of macrophages infected with Mtb to
T cell and NK cell-mediated elimination and characterize the accompanying immunoevasion mechanisms, the
second Research Area will characterize the interactions between Mtb-infected macrophage and antigen-specific
T cells and NK cells. Finally, as Dr. Clayton’s published work suggests that inefficient killing of macrophages is
a result of resistance to apoptosis-inducing T cell-derived granzymes, the third Research Area will probe for the
identities of granzyme inhibitors expressed by macrophages, and subsequently knockout candidate genes to
enhance T and NK cell-mediated killing of infected macrophages. Together, these studies will provide insight
into whether targeting natural granzyme inhibitors can provide a common method to enhance immune-mediated
clearance of macrophages infected by different pathogens. The goals of this proposal are highly relevant to the
mission of NIAID, and will enhance our understanding of distinct pathogen-specific immunoevasion mechanisms
and those inherently characteristic of macrophages that allow for pathogen persistence despite strong immune
responses. Ultimately, this work will aid the design and development of therapeutics to target HIV and Mtb
infection in macrophages, and will potentiate future studies to assess how macrophage-mediated
immunoevasion contributes to persistence of other pathogens, including human cytomegalovirus.

## Key facts

- **NIH application ID:** 10460397
- **Project number:** 5DP2AI154438-02
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Kiera L. Clayton
- **Activity code:** DP2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $502,500
- **Award type:** 5
- **Project period:** 2021-08-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10460397

## Citation

> US National Institutes of Health, RePORTER application 10460397, Characterizing Macrophages as "Hide-Outs" for Chronic Pathogens (5DP2AI154438-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10460397. Licensed CC0.

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