# Stenotrophomonas Maltophilia Type IV Secretion: Modulator of Both Host-Cell Apoptosis and Interbacterial Killing

> **NIH NIH R21** · NORTHWESTERN UNIVERSITY · 2020 · $188,839

## Abstract

PROJECT SUMMARY
Gram-negative Stenotrophomonas maltophilia (Sm) is recently recognized as an important opportunistic and
nosocomial pathogen. Pneumonia is the most frequent expression of Sm infection, although Sm is also linked
to bloodstream, eye, skin, and urinary-tract infections. Sm is also an independent risk factor for lung
exacerbations in CF patients. Despite the emergence of Sm as a pathogen, due in part to its drug resistance,
our understanding of Sm virulence is very limited. Sm is considered an extracellular pathogen, capable of
attaching to a variety of host cells, and we have recently shown that Sm encodes a type II secretion system
which secretes a protease that triggers apoptosis in lung epithelia. After examining the genome database, we
determined that Sm likely also encodes a type IV secretion system (T4SS). In other bacteria, T4SS mediate
the delivery of DNA and/or protein “effectors” into eukaryotic and/or bacterial targets. In order to understand
the role of Sm T4SS, we made a mutant devoid of activity by eliminating the VirB10 component of the
secretion apparatus, and then tested the mutant in various infection assays. The mutant induced a higher level
of apoptosis upon infection of human lung epithelial cells, suggesting that a Sm T4SS effector(s) has anti-
apoptotic activity. However, when we infected human macrophages, the virB10 mutant triggered a lower level
of apoptosis, implying that Sm T4SS also elaborates a pro-apoptotic factor(s). In both cases, the effect of
T4SS required Sm contact with the host cell. The importance of Sm T4SS was also evident when we
assessed virB10 mutant growth in the lungs of mice. Moreover, T4SS promoted the growth of Sm when the
bacterium was co-cultured with E. coli or P. aeruginosa, suggesting that another effector(s) has anti-bacterial
activity. Our bioinformatic analysis of the Sm genome revealed ~18 putative T4SS effectors, including a
homolog of a eukaryotic peptidase as well as novel proteins that lack similarity to known proteins. Two-hybrid
analysis confirmed that these effectors indeed bind to the T4SS apparatus. Thus, we posit that, following Sm
attachment to target cell surfaces, the T4SS apparatus delivers multiple (novel) effectors into the cytoplasm,
with some of those effectors inducing or modulating death pathways. That a T4SS can have anti- and pro-
apoptotic effects on different targets, including both human and bacterial cells, has, to our knowledge, not been
seen before. Thus, we propose to identify the effectors that i) mediate the pro- and anti-apoptotic action on
human cells (Aim 1), and ii) impact other bacteria as well as amoebal hosts for Sm (Aim 2). Besides giving
much-needed understanding of Sm, the data obtained will have implications for the many undefined T4SS that
exist in the genomes of other bacteria and aid in our appreciation of T4SS as a target for new anti-microbials.

## Key facts

- **NIH application ID:** 9870876
- **Project number:** 5R21AI139596-02
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** NICHOLAS P CIANCIOTTO
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $188,839
- **Award type:** 5
- **Project period:** 2019-02-13 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9870876

## Citation

> US National Institutes of Health, RePORTER application 9870876, Stenotrophomonas Maltophilia Type IV Secretion: Modulator of Both Host-Cell Apoptosis and Interbacterial Killing (5R21AI139596-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9870876. Licensed CC0.

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