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THE RESIDENT MICROBIOTA LINING THE GUT MUCOSA PROVIDES A CRUCIAL HOST DEFENSE STRATEGY TERMED COLONIZATION RESISTANCE, WHICH INCLUDES DIRECT PATHWAYS OF INTERBACTERIAL ANTAGONISM, SUCH AS TYPE VI SECRETION SYSTEMS (T6SS), AND INDIRECT PATHWAYS OF ENHANCED IMMUNITY. THE FULL COMPLEMENT OF HOST COLONIZATION RESISTANCE MECHANISMS REMAINS POORLY CHARACTERIZED. RECENT EVIDENCE SUGGESTS THAT GUT-ASSOCIATED BACTERIA RESIDING IN THE LUNG (GALB) MAY ALSO PARTICIPATE IN INDIRECT COLONIZATION RESISTANCE BY TRAINING IMMUNE CELLS TO CROSS-PROTECT THE HOST AGAINST INVADING BACTERIA ("TRAINED IMMUNITY"). INTERVENTIONS THAT MANIPULATE THE LUNG MICROBIOTA MAY ENHANCE HOST RESISTANCE TO A VARIETY OF PATHOGENS.SALMONELLA DUBLIN (SED) IS A ZOONOTIC, CATTLE-ADAPTED PATHOGEN THAT EFFICIENTLY COLONIZES THE GUT AND PREFERENTIALLY CAUSES PNEUMONIA IN CALVES. IT IS ALSO AN EMERGING FOODBORNE INFECTIOUS DISEASE IN HUMANS, WITH RECENT INCREASES IN CASE SEVERITY AND MULTI-DRUG RESISTANCE. THIS RESEARCH PROJECT AIMS TO FURTHER UNDERSTAND HOW SED INTERACTS WITH THE HOST MICROBIOTA AND IMMUNE SYSTEM TO UNDERMINE COLONIZATION RESISTANCE WITHIN THE CALF GUT AND LUNG. I HYPOTHESIZE THAT GALB STIMULATES PULMONARY IMMUNITY BY TRAINING MACROPHAGES AND THAT SED REQUIRES T6SSS, TO OUTCOMPETE THE MICROBIOTA IN THE GUT AND LUNG AND TO IMPEDE PULMONARY COLONIZATION RESISTANCE BY HINDERING "TRAINED IMMUNITY". MY ULTIMATE GOAL IS TO UNDERSTAND WHETHER GALB TRAIN PULMONARY MACROPHAGES TO RESIST SED INFECTION AND TO ESTABLISH WHETHER SED NEED T6SS TO OVERCOME COLONIZATION RESISTANCE IN CATTLE. I WILL COLLECT LOWER RESPIRATORY TRACT FLUID FROM HEALTHY CALVES TO CORRELATE GALB WITH IMMUNE CELLS AND IMMUNE FUNCTION. I WILL ALSO USE A CALF MODEL OF ACUTE SED COLONIZATION TO DETERMINE WHETHER T6SS IS IMPORTANT FOR GUT COLONIZATION. I WILL USE IN VITRO COMPETITIVE EXPERIMENTS TO DETERMINE WHETHER T6SS IS IMPORTANT FOR SED TO OUTCOMPETE GALB AND WHETHER GALB ARE ABLE TO INFLUENCE THE FUNCTION OF ALVEOLAR MACROPHAGES INFECTED WITH SED IN CELL CULTURE. GIVEN THE IMPORTANCE OF SED TO ANIMAL HEALTH AND FOOD SAFETY, IT IS CRUCIAL TO UNDERSTAND HOW SED SUBVERTS HOST IMMUNITY. FURTHERMORE, UNDERSTANDING THE ROLE OF GALB IN LUNG IMMUNE FUNCTION WILL HAVE BROAD IMPACT ON PNEUMONIA PREVENTION IN CALVES. THIS WORK WILL CONTRIBUTE FOUNDATIONAL KNOWLEDGE TO THE INTERACTIONS BETWEEN THE HOST, MICROBIOTA AND PATHOGEN, WHICH ARE CRUCIAL FOR STRATEGIZING NOVEL CALF HEALTH INTERVENTIONAL THERAPIES.

$86,239FY2021National Institute of Food and AgricultureUSDA

University Of Wisconsin System, Madison WI

Investigators

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THE RESIDENT MICROBIOTA LINING THE GUT MUCOSA PROVIDES A CRUCIAL HOST DEFENSE STRATEGY TERMED COLONIZATION RESISTANCE, WHICH INCLUDES DIRECT PATHWAYS OF INTERBACTERIAL ANTAGONISM, SUCH AS TYPE VI SECRETION SYSTEMS (T6SS), AND INDIRECT PATHWAYS OF ENHANCED IMMUNITY. THE FULL COMPLEMENT OF HOST COLONIZATION RESISTANCE MECHANISMS REMAINS POORLY CHARACTERIZED. RECENT EVIDENCE SUGGESTS THAT GUT-ASSOCIATED BACTERIA RESIDING IN THE LUNG (GALB) MAY ALSO PARTICIPATE IN INDIRECT COLONIZATION RESISTANCE BY TRAINING IMMUNE CELLS TO CROSS-PROTECT THE HOST AGAINST INVADING BACTERIA ("TRAINED IMMUNITY"). INTERVENTIONS THAT MANIPULATE THE LUNG MICROBIOTA MAY ENHANCE HOST RESISTANCE TO A VARIETY OF PATHOGENS.SALMONELLA DUBLIN (SED) IS A ZOONOTIC, CATTLE-ADAPTED PATHOGEN THAT EFFICIENTLY COLONIZES THE GUT AND PREFERENTIALLY CAUSES PNEUMONIA IN CALVES. IT IS ALSO AN EMERGING FOODBORNE INFECTIOUS DISEASE IN HUMANS, WITH RECENT INCREASES IN CASE SEVERITY AND MULTI-DRUG RESISTANCE. THIS RESEARCH PROJECT AIMS TO FURTHER UNDERSTAND HOW SED INTERACTS WITH THE HOST MICROBIOTA AND IMMUNE SYSTEM TO UNDERMINE COLONIZATION RESISTANCE WITHIN THE CALF GUT AND LUNG. I HYPOTHESIZE THAT GALB STIMULATES PULMONARY IMMUNITY BY TRAINING MACROPHAGES AND THAT SED REQUIRES T6SSS, TO OUTCOMPETE THE MICROBIOTA IN THE GUT AND LUNG AND TO IMPEDE PULMONARY COLONIZATION RESISTANCE BY HINDERING "TRAINED IMMUNITY". MY ULTIMATE GOAL IS TO UNDERSTAND WHETHER GALB TRAIN PULMONARY MACROPHAGES TO RESIST SED INFECTION AND TO ESTABLISH WHETHER SED NEED T6SS TO OVERCOME COLONIZATION RESISTANCE IN CATTLE. I WILL COLLECT LOWER RESPIRATORY TRACT FLUID FROM HEALTHY CALVES TO CORRELATE GALB WITH IMMUNE CELLS AND IMMUNE FUNCTION. I WILL ALSO USE A CALF MODEL OF ACUTE SED COLONIZATION TO DETERMINE WHETHER T6SS IS IMPORTANT FOR GUT COLONIZATION. I WILL USE IN VITRO COMPETITIVE EXPERIMENTS TO DETERMINE WHETHER T6SS IS IMPORTANT FOR SED TO OUTCOMPETE GALB AND WHETHER GALB ARE ABLE TO INFLUENCE THE FUNCTION OF ALVEOLAR MACROPHAGES INFECTED WITH SED IN CELL CULTURE. GIVEN THE IMPORTANCE OF SED TO ANIMAL HEALTH AND FOOD SAFETY, IT IS CRUCIAL TO UNDERSTAND HOW SED SUBVERTS HOST IMMUNITY. FURTHERMORE, UNDERSTANDING THE ROLE OF GALB IN LUNG IMMUNE FUNCTION WILL HAVE BROAD IMPACT ON PNEUMONIA PREVENTION IN CALVES. THIS WORK WILL CONTRIBUTE FOUNDATIONAL KNOWLEDGE TO THE INTERACTIONS BETWEEN THE HOST, MICROBIOTA AND PATHOGEN, WHICH ARE CRUCIAL FOR STRATEGIZING NOVEL CALF HEALTH INTERVENTIONAL THERAPIES. · GrantIndex