INVASION OF THE ENTERIC NERVOUS SYSTEM BY NEUROTROPIC LISTERIA MONOCYTOGENES - LISTERIA MONOCYTOGENES (LM)…

Assistance award details

Assistance award identifier

ASST_NON_R01AI167953_075

FAIN

R01AI167953

Recipient

UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE

Awarding agency

Department of Health and Human Services

Funding agency

Department of Health and Human Services

Assistance listing (CFDA)

93.855

Total obligated

$2,376,885

Period

Jul 1, 2023 – Jun 30, 2028

Fiscal year

2023

Place of performance state

KY

Source file

FY2023_All_Assistance_Full_20261006.zip

Description

INVASION OF THE ENTERIC NERVOUS SYSTEM BY NEUROTROPIC LISTERIA MONOCYTOGENES - LISTERIA MONOCYTOGENES (LM) ARE GRAM-POSITIVE, FACULTATIVE INTRACELLULAR BACTERIA THAT CAUSE TWO TYPES OF BRAIN INFECTIONS IN HUMANS: DIFFUSE (MENINGITIS/MENINGOENCEPHALITIS) AND FOCAL BRAINSTEM (RHOMBENCEPHALITIS). MENINGITIS OCCURS IN THE SETTING OF IMMUNE COMPROMISE, LIKELY DUE TO THE FAILURE OF THE IMMUNE SYSTEM TO LIMIT EXPONENTIAL GROWTH OF LM IN TISSUES SUCH AS SPLEEN OR LIVER. THIS LEADS TO HIGH TITER BACTEREMIA AND EITHER DIRECT INVASION OF THE BLOOD-BRAIN-BARRIER (BBB) OR “STEALTH TRANSPORT” OF LM ASSOCIATED WITH MYELOID-DERIVED CELLS THAT CROSS THE BBB. IN CONTRAST, RHOMBENCEPHALITIS IS AN INFECTION OF A DELAYED NATURE THAT OCCURS IN YOUNG, OTHERWISE HEALTHY IMMUNE COMPETENT PEOPLE, WHICH SUGGESTS THAT THE INFECTION IS DEPENDENT ON BACTERIALLY ENCODED NEUROVIRULENCE FACTORS. THE CENTRAL HYPOTHESIS OF THIS PROPOSAL IS THAT THE VIRULENCE FACTORS WHICH DEFINE NEUROTROPISM DURING RHOMBENCEPHALITIS MEDIATE CRITICAL EARLY EVENTS IN THE INTESTINES, RATHER THAN IN THE BRAIN. SUPPORT FOR THIS HYPOTHESIS COMES FROM OUR PRELIMINARY DATA SHOWING THAT WHEN THE NEUROTROPIC LM ARE INJECTED INTRAVENOUSLY (BYPASSING THE GUT PHASE OF THE INFECTION), THEY DO NOT DISSEMINATE TO THE BRAIN. IN ADDITION, OTHERS SHOWED THAT RHOMBENCEPHALITIS ISOLATES DID NOT HAVE AN INCREASED ABILITY TO SURVIVE AND REPLICATE IN BOVINE ORGANOTYPIC BRAIN SLICES EX VIVO RELATIVE TO OTHER LM STRAINS. UNTIL RECENTLY, RHOMBENCEPHALITIS COULD BE STUDIED ONLY IN COWS OR SHEEP DUE TO THE LACK OF A SMALL ANIMAL MODEL OF LM BRAINSTEM INFECTIONS. HOWEVER, WE RECENTLY SHOWED THAT SOME CLINICAL ISOLATES OF LM (UKVDL9 AND SD4000) COULD PREFERENTIALLY COLONIZE THE BRAINSTEMS OF MICE LATE IN THE COURSE OF INFECTION, WITHOUT REACHING HIGH TITER IN THE BLOOD. BOTH OF THE NEUROTROPIC STRAINS WE REPORTED BELONG TO LINEAGE III, THE SMALLEST AND LEAST CHARACTERIZED GROUP OF LM ISOLATES. THE GOAL OF THIS PROPOSAL IS TO DEFINE THE FACTORS