# How group A Streptococcus M1 protein resists cathelicidins

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $196,875

## Abstract

We seek to understand how group A Streptococcus defeats one of the primary human defenses against
infection, the cationic antimicrobial peptide LL-37. Group A Streptococcus (GAS, S. pyogenes) is a leading
cause of global morbidity and mortality. With an estimated >500,000 deaths annually, GAS ranks among the
top 10 causes of mortality from infectious disease. GAS is responsible for acute invasive diseases, such as
streptococcal toxic shock syndrome (STSS) and necrotizing fasciitis (NF), which have alarmingly high mortality
rates (as high as 80% in some cases). The leading cause of acute invasive GAS disease worldwide for
more than 30 years has been a globally disseminated subclone of the GAS M1T1 serotype. A critical
virulence determinant of the GAS M1T1 serotype strain is the M1 protein. We have shown recently in
LaRock et al. (Cell Host & Microbe 2015) that one of the critical functions of the M1 protein is detoxification of
the human cathelicidin LL-37, a cationic antimicrobial peptide. LL-37 forms amphipathic α-helices, and
functions, like other amphipathic α-helical cationic antimicrobial peptides, by inserting into bacterial plasma
membranes and causing lysis. The M1 protein enables GAS M1 serotype strains to resist killing by LL-37,
and to resist killing within neutrophil extracellular traps (NETs), where LL-37 is abundant. The M1 protein does
this by sequestering LL-37 into a ‘protein trap’, which prevents LL-37 from interacting with its target of
action, the bacterial membrane. Importantly, we have found that the virulence contribution of the M1 protein
in a murine subcutaneous wound infection model is almost entirely attributable to its interaction with
the murine ortholog of LL-37, CRAMP. How the M1 protein binds and detoxifies LL-37 is unknown, and is
the focus of this proposal. Our specific aims are to (1) Identify the M1 amino acids responsible for binding
and detoxifying LL-37, and (2) Elucidate M1-cathelicidin interactions at the atomic level. This second aim
is a high-risk, high-reward aim that is in perfect alignment with the goals of the R21 mechanism.
Knowledge gained from this study will be applicable to the design of strategies aimed at restoring the
antimicrobial power of LL-37 on GAS M1 strains. This is a significant goal as the GAS M1 strain is the
predominant cause of invasive GAS disease in the US, surpassing the next most frequent GAS M type strain
by more than 3-fold, and as noted above, an M1T1 serotype strain is the predominant cause of invasive GAS
disease worldwide. Furthermore, it seems highly unlikely that the M1 protein would be the only M protein to
bind and detoxify LL-37. A number of invasive GAS strains are resistant to the action of LL-37, and indeed we
have direct evidence that other M proteins bind and detoxify LL-37. Thus, this project will not only have direct
impact on combatting the widespread and medically significant GAS M1 strain, but will also likely have broader
implications.

## Key facts

- **NIH application ID:** 9878057
- **Project number:** 5R21AI144901-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** PARTHO GHOSH
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $196,875
- **Award type:** 5
- **Project period:** 2019-03-01 → 2021-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9878057

## Citation

> US National Institutes of Health, RePORTER application 9878057, How group A Streptococcus M1 protein resists cathelicidins (5R21AI144901-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9878057. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*