# Host-pathogen interactions during hospital adaptation of MRSA

> **NIH NIH R01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2020 · $829,843

## Abstract

PROJECT SUMMARY
Our long-term goal is to transform knowledge of nosocomial evolution into successful management strategies
to confront the growing problem of methicillin-resistant Staphylococcus aureus (MRSA). Here we focus on
understanding the different ways by which community- and hospital-associated MRSA (CA- and HA-MRSA)
interact with components of the innate immune system to cause different epidemiology and outcomes of
infection. Work by us and others suggests that adaptation of MRSA to hospital conditions often involves an
interplay of mutations that coordinately confer antibiotic resistance and attenuate virulence. How the resulting
changes affect host–pathogen interactions at the cellular and molecular levels is poorly understood. Given that
macrophages are central mediators of MRSA uptake and dissemination, we will identify differential
mechanisms governing CA- and HA-MRSA intracellular detection by, and survival in, host macrophages. Our
preliminary results indicate that the production of cytolytic toxins, which is repressed in HA-MRSA and
enhanced in CA-MRSA, enable intracellular MRSA to overcome the expression of macrophage immunity and
enhance pathogen survival. At the same time, attenuated cytolytic activity may be advantageous in certain
situations, such as in hospital-associated infections, because suppression of inflammatory activity might avoid
detection of the pathogen or limit damage to it by the host immune system. The complexity of the selective
forces that drive these traits underscores the need for a comprehensive, systems approach to examine the role
of host and pathogen capabilities in determining how MRSA subsets differentially modulate immune
responses. Given that host–pathogen interactions are pleotropic and interconnected, analysis of individual
genes alone cannot explain the cellular responses to infection, much less the bacterial responses. We
leverage the power of systems-level analysis of CA-MRSA, transitional CA-MRSA, and HA-MRSA to
understand the interactions between MRSA and macrophages during infection. We will interpret profiling
results in the context of measures of pathogen versus host success. These include the fate of intracellular
bacteria during infection of macrophages in vitro and in murine models specifically designed to reflect
conditions in hospitalized patients (disruption of immune functions permit MRSA strains that lack full virulence
to cause infection). We will prepare bacterial mutants of relevant pathways to recreate the capabilities of CA-
or HA-MRSA strains. We will also perturb specific networks, both in infected human macrophages and in
infected murine models, to identify loci where the pathways can be manipulated. By determining the similarities
and differences in the host and pathogen transcriptional programs during macrophage infection, comparative
analyses between CA- and HA-MRSA will transform our understanding of the pathogenesis of both forms of
MRSA. The output will be a mechani...

## Key facts

- **NIH application ID:** 10004561
- **Project number:** 5R01AI137336-02
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** BO SHOPSIN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $829,843
- **Award type:** 5
- **Project period:** 2019-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10004561

## Citation

> US National Institutes of Health, RePORTER application 10004561, Host-pathogen interactions during hospital adaptation of MRSA (5R01AI137336-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10004561. Licensed CC0.

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