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Biology of hypervirulent Klebsiella pneumoniae translocation from the gastrointestinal tract

Award Number: R21AI166642
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 11/01/2021
PERIOD OF PERFORMANCE END DATE: 10/31/2024

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Biology of hypervirulent Klebsiella pneumoniae translocation from the gastrointestinal tract - Description. Klebsiella pneumoniae (Kpn) is a significant source of hospital-acquired infections. As Kpn has acquired multi- drug resistance, it has become even more challenging to treat. Another concern is the increase in isolation of strains termed as hypervirulent Klebsiella pneumoniae or hvKpn known to cause disease manifestations in a community setting. These isolates have acquired a repertoire of virulence factors, which allow them to cause disease in immunocompetent individuals. Recently, multiple fatal hospital outbreaks have been linked to multi- drug resistant hvKpn isolates. Epidemiological studies suggest that gastrointestinal (GI) colonization of hvKpn is a major reservoir through which it can translocate to sterile sites and cause disease manifestations in the colonized host. However, hvKpn gut colonization has not been the focus of previous studies as a tractable model for gastrointestinal (GI) colonization and translocation did not exist. We recently developed a murine model of Kpn and hvKpn GI colonization, achieved without the requirement of antibiotics. Our tractable model allows us a better understanding of the dynamic interactions of Kpn with the host with an intact gut microbiome. Moreover, development of pyogenic liver abscess a trademark of hvKpn infections in humans was also observed in our GI model of colonization. Thus, we propose that hvKpn uses specific pathways to promote its translocation, facilitated by its virulence determinants. These determinants can serve as novel targets for the prevention of the development of the disease state. More recently, with our animal model, we observed translocation to occur 24 hours post-GI colonization. However, the exact route(s) taken by hvKpn and the role of specialized enterocytes (M-cells) in translocation remains to be elucidated. Thus, in Aim #1, we will carry out in vitro cell line assays to determine the pathway(s) taken by hvKpn to promote its translocation. Secondly, we will determine the host M-cells' role in promoting hvKpn translocation using knockout mice strains. Our data suggest that hvKpn specific iron acquisition molecule aerobactin (iuc) contributes towards the translocation process. Even though iuc plays a role in translocation, an iuc mutant does not entirely abrogate it, suggesting that other factors are critical for translocation. By taking an in vivo novel high-throughput approach in Aim #2, we will identify putative hvKpn factors that promote its translocation. Results from our studies will not only provide an understanding of the translocation process but also identify putative translocation determinants, which could be potential targets to reduce the hvKpn disease burden.


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: 2025 ( Subtotal = -$997 )
2025	2023	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Allergy and Infectious Diseases Research	000	2	4/16/2025	NON-COMPETING CONTINUATION	-$997
														Subtotal = -$997

Issue Date FY: 2023 ( Subtotal = $193,750 )
2023	2023	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Allergy and Infectious Diseases Research	000	2	10/21/2022	NON-COMPETING CONTINUATION	$193,750
														Subtotal = $193,750

Issue Date FY: 2022 ( Subtotal = $232,500 )
2022	2022	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Allergy and Infectious Diseases Research	000	1	10/26/2021	NEW	$232,500
														Subtotal = $232,500

Grand Total All Awards = $425,253

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Biology of hypervirulent Klebsiella pneumoniae translocation from the gastrointestinal tract

Award Number: R21AI166642

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 11/01/2021

PERIOD OF PERFORMANCE END DATE: 10/31/2024

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