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How prophages impact pathogen survival during mammalian infection

Award Number: F32AI202957
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 02/06/2027
PERIOD OF PERFORMANCE END DATE: 02/05/2028

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How prophages impact pathogen survival during mammalian infection - Project Summary The central objective of the proposed research is to understand how prophages contribute to pathogen survival and antibiotic recalcitrance during infection. Pathogenic bacteria harbor multiple latent viruses called prophages. Prophages confer fitness benefits by expressing cargo genes, eg. virulence factors such as toxins and anti-phage defense systems but can also reactivate upon exposure to antimicrobials encountered by the bacteria during infection. Successful bacterial pathogens that survive in the mammalian host must control prophage reactivation; yet the mechanisms of prophage control are poorly understood. Recent work from the Helaine lab discovered that prophages of Salmonella enterica inhibit one another via encoded anti-phage defense systems, blocking cell lysis. Importantly, these anti-phage defense systems function through a bacteriostatic effect that prevents phage takeover of the bacterium but renders the bacterium non-growing. Klebsiella pneumoniae (Kp) is a facultative intracellular pathogen of pressing clinical concern due to its high rates of antibiotic resistance. Kp lacks canonical virulence factors and causes disease through effective immune evasion and survival during exposure to host antimicrobials that are known inducers of prophages. Therefore, Kp success hinges on suppression of prophage-induced cell death; however, no mechanisms of prophage control are known. We found that clinical isolates of Kp survive remarkably well within macrophages despite experiencing high levels of oxidative stress; a known inducer of prophages. In Kp, a single prophage Kp1 is responsible for cell lysis and death but is inhibited by a new anti-phage defense system called RemS encoded on the prophage Kp2. RemS exerts a bacteriostatic effect, but its mechanism of action is unknown. Aim 1 will determine how RemS exerts a bacteriostatic effect on Kp and characterize how it blocks Kp1 lysis and cell death. Aim 2 will reveal how Kp survives within macrophages by a) identifying novel Kp virulence factors, focusing on prophages as reservoirs and b) assess the contribution of prophage competition systems (RemS) to intramacrophage survival and antibiotic recalcitrance. Upon completion the expected outcome of this research is to determine the importance of prophages for Kp infections of mammalian hosts.


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 = $77,782 )
2026	2026	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	1	8/6/2026	NEW	$77,782
														Subtotal = $77,782

Grand Total All Awards = $77,782

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How prophages impact pathogen survival during mammalian infection

Award Number: F32AI202957

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 02/06/2027

PERIOD OF PERFORMANCE END DATE: 02/05/2028

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