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Molecular host determinants of spotted fever group rickettsial infection

Award Number: K99AI192941
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 08/18/2026
PERIOD OF PERFORMANCE END DATE: 06/30/2028

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Molecular host determinants of spotted fever group rickettsial infection - PROJECT SUMMARY/ABSTRACT The global incidence of tickborne human vascular endothelial diseases caused by obligate intracellular bacterial pathogens in the Rickettsia spotted fever group (SFG) has increased dramatically in the 21st century. Since their entire infection cycle takes place within the host cytoplasm, SFG Rickettsia spp. exhibit specialized biology that is deeply interconnected with the host, making them excellent discovery models for unique host-pathogen interactions and rickettsial dependencies on host processes that may be promising therapeutic targets. However, since SFG rickettsiae cannot be cultured extracellularly or easily genetically manipulated, they are severely understudied relative to their public health burden. Host-directed perturbation and profiling tools are attractive approaches to circumvent these obstacles, but these techniques have only rarely been applied to Rickettsia spp. As a result, we have a highly limited understanding of how host factors shape rickettsial infection. To address this gap, I performed the first genome-scale screen for host regulators of mammalian cell infection by the model SFG species Rickettsia parkeri. This screen revealed dozens of novel host determinants of R. parkeri intracellular fitness. In pursuit of specific hits from the screen, I hypothesize that SFG rickettsial intracellular fitness relies on direct and indirect interactions with host protein folding and lipid metabolic factors. In Aims 1 and 2, I will dissect a new axis of host-pathogen interaction I uncovered in the screen, where the host proline isomerase PPIA/cyclophilin A directly interacts with the R. parkeri surface virulence factor Sca2 and enables its surface translocation. Then, in Aim 3, I will decipher how competing lipid biosynthesis pathways with contrasting screen phenotypes interact during infection, and profile broader host metabolic responses to R. parkeri to identify new host metabolic pathways underlying pathogen fitness in endothelial cells. Collectively, these studies will provide fundamental new insights into host-rickettsial interactions. By investigating molecular host dependencies that underlie SFG rickettsial infection, my work will also uncover promising new avenues for therapeutic development against this group of emerging and re-emerging pathogens. Taking place in the highly collaborative training environment at MIT, the proposed work will provide me with outstanding opportunities to develop new expertise in metabolomics and endothelial biology. In addition to formal scientific and professional development training, the world-class mentors and advisors supporting this work will provide me with complementary scientific expertise and career guidance to accelerate my transition to an independent principal investigator position.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $185,472 )
2026	2026	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Allergy and Infectious Diseases Research	000	1	8/18/2026	NEW	$185,472
														Subtotal = $185,472

Grand Total All Awards = $185,472

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Molecular host determinants of spotted fever group rickettsial infection

Award Number: K99AI192941

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 08/18/2026

PERIOD OF PERFORMANCE END DATE: 06/30/2028

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