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Principal Investigator: BRIAN L WEISS
Organization: YALE UNIVERSITY
Fiscal Year: 2024
Award: $190,604
Funding agency: National Institute of Allergy and Infectious Diseases
The midgut of most arthropods is lined by a peritrophic matrix (PM) that is composed of a chitin backbone upon
which assemble a variety of glycosaminoglycans and proteins. The PM serves a defensive role within arthropods
by protecting their midgut epithelia from abrasive food particles, regulating the movement of ingested toxins, and
serving as a physical barrier against pathogen infection establishment. Some vector-borne protozoan pathogens,
including mosquito-transmitted Plasmodium and sand fly-transmitted Leishmania, secrete chitinases that can
degrade PM-associated chitin. However, tsetse fly-transmitted African trypanosomes do not produce chitinase,
and the mechanism(s) these parasites use to circumvent tsetse’s PM are poorly understood.
In addition to potentially being infected with African trypanosomes, all tsetse flies harbor a taxonomically
variable community of endosymbiotic bacteria. The success of trypanosome transmission through the tsetse
vector depends in part on physiological interactions between the fly and these bacteria. One of tsetse’s
endosymbionts, Sodalis glossinidius, exhibits a homogeneous distribution within all laboratory colonized flies
and a heterogeneous distribution within and between wild fly populations. Several independent field and
laboratory-based studies have repeatedly demonstrated a positive correlation between the presence and density
of Sodalis in tsetse’s midgut and the ability of trypanosomes to successfully establish an infection in the fly. The
mechanisms that underlie this correlation have never been determined. In this application our interdisciplinary
research team will address the hypothesis that a Sodalis secreted endochitinase degrades the chitinous
backbone of tsetse’s PM. We speculate that Sodalis-mediated degradation of PM-associated chitin facilitates
trypanosome infection establishment in two ways. First, this process would compromise the structural integrity
of the PM, thus making it easier for trypanosomes to cross. Second, chitin catabolism results in the production
of N-acetyl-D-glucosamine, which is a potent inhibitor of trypanocidal lectins. We propose to use Sodalis mutants
that cannot produce endochitinase to functionally characterize the tripartite relationship between the bacterium,
tsetse’s PM, and trypanosome infection establishment in the fly’s midgut. Additionally, we propose to use field
captured tsetse flies to determine if their Sodalis produce endochitinase that mediates the structural integrity of
their tsetse host’s PM. Completion of the experiments proposed in this application will increase our
understanding of the basic physiological mechanisms that mediated trypanosome transmission through the
tsetse vector and may have translational implications towards the development of novel disease control
strategies. Additionally, knowledge obtained herein will be applicable to other arthropod vector model systems
(e.g., mosquitoes, ticks, sandflies) that house midgut-associated bacteria and have a PM that pathogens must
cross in order to be transmitted to a new vertebrate host.
Terms: <2-Amino-2-Deoxyglucose><2-amino-2-deoxy-D-glucose><African><Animals><Arthropod Vectors><Arthropoda><Arthropods><Bacteria><Biologic Models><Biological Models><Catabolism><Chitin><Chitinase><Chromosomes><Communities><Culicidae><Cyclicity><Data><Development><Disease><Disease Vectors><Disorder><Environment><Enzyme Gene><Enzymes><Epidemiology><Epithelium><Exhibits><Flies><Food><Gene Modified><General Taxonomy><Genes><Genetic><Genome><Geography><Glossina><Glucosamine><Glycosaminoglycans><Goals><Houseflies><Human><In Vitro><Infection><Ingestion><Interdisciplinary Research><Interdisciplinary Study><Investigation><Ixodida><Kenya><Knock-out><Knockout><Knowledge><Laboratories><Learning><Lectin><Leishmania><Mediating><Midgut><Model System><Modeling><Modern Man><Mosquitoes><Movement><Mucopolysaccharides><Multidisciplinary Collaboration><Multidisciplinary Research><Musca domestica><Outcome><Parasites><Pathogenicity><Periodicity><Phlebotominae><Physiologic><Physiological><Physiology><Plasmodium><Population><Prevalence><Process><Production><Proteins><Research><Rhythmicity><Role><Salivary Glands><Salivary Glands Head and Neck><Spinal Column><Spine><Structure><Symbiosis><T brucei><T. brucei><Taxonomy><Ticks><Toxin><Transmission><Trypanocidal Agents><Trypanocidal Drugs><Trypanocides><Trypanosoma><Trypanosoma brucei><Trypanosoma brucei brucei><Trypanosome><Trypanosomicidal Agents><Trypanosomicides><Tsetse Flies><Vertebral column><Work><backbone><body movement><commensalism><density><developmental><disease control><disorder control><endosymbiont><epidemiologic><epidemiological><experiment><experimental research><experimental study><experiments><extracellular><fly><gene modification><genetically modified><house fly><ingest><inhibitor><insight><migration><mutant><new approaches><novel><novel approaches><novel strategies><novel strategy><overexpress><overexpression><particle><pathogen><sandfly><social role><socio-economic><socio-economically><socioeconomically><socioeconomics><success><transmission process><vector><vector competence><vector-borne><vectorborne><vectorial competence>