In immunocompetent individuals, non-typhoidal Salmonella serotypes (NTS) are associated with gastroenteritis, a localized infection with low mortality manifesting as diarrhea, vomiting and intestinal cramping. However, in immunocompromised individuals, a breach of mucosal barrier functions can result in the development of a life threatening bacteremia. The incidence of disseminated NTS infections has reached epidemic status in sub-Saharan Africa, where these infections are associated with bacteremia, meningitis and sepsis, and often have a fatal outcome. In young children, epidemiologic studies have determined that severe malaria is an important immunocompromising condition predisposing to NTS bacteremia. In children with severe Plasmodium falciparum malaria the prevalence of disseminated NTS infections is particularly striking. However, the immune defects caused by severe malaria that increase the risk of developing NTS bacteremia, are not known. The objective of this application is to use our recently developed murine co-infection model of malaria and NTS to identify effects of malaria on the immune response to a subsequent bacterial infection. Our central hypothesis is that in pediatric patients, underlying malaria parasite infection leads to both a breach in intestinal barrier function and a reduced ability to check growth at systemic sites by interfering with neutrophil recruitment and bacteriocidal activity. We will test our hypothesis by (i) identifying mechanisms by which underlying malaria parasite infection compromises mucosal inflammation, and (ii) determining effects of malaria parasite infection on immunologic mechanisms that control bacterial organ loads. The fact that NTS/malaria co-infections are understudied, even though they represent a major cause of mortality in sub-Saharan Africa, makes the proposed work highly significant. We expect that the proposed research will provide important and novel insights into specific immune mechanisms that are important for mucosal barrier function to NTS infection. Further, the results of our proposed studies are likely to provide novel paradigms of how polymicrobial infections affect disease outcome.
Nontyphoidal Salmonella serotypes (NTS), which usually cause diarrheal disease in immunocompetent individuals, are a leading cause of bacteremia in immunocompromised individuals in Sub-Saharan Africa. Severe malarial anemia is a major risk factor in African children for dissemination of NTS from the intestine to the bloodstream. We expect that our proposed research to identify the immune defects in pediatric malaria patients predisposing them to NTS bacteremia will provide important new insights into specific immune mechanisms that are important for maintaining the intestinal barrier function to bacteria and broaden our understanding of how simultaneous infection with multiple pathogens affect disease outcome.
|Lokken, Kristen L; Stull-Lane, Annica R; Poels, Kikkie et al. (2018) Malaria parasite-mediated alteration of macrophage function and increased iron availability predispose to disseminated non-typhoidal Salmonella infection. Infect Immun :|
|Carden, Sarah E; Walker, Gregory T; Honeycutt, Jared et al. (2017) Pseudogenization of the Secreted Effector Gene sseI Confers Rapid Systemic Dissemination of S. Typhimurium ST313 within Migratory Dendritic Cells. Cell Host Microbe 21:182-194|
|Singletary, Larissa A; Karlinsey, Joyce E; Libby, Stephen J et al. (2016) Loss of Multicellular Behavior in Epidemic African Nontyphoidal Salmonella enterica Serovar Typhimurium ST313 Strain D23580. MBio 7:e02265|
|Lopez, Christopher A; Miller, Brittany M; Rivera-Chávez, Fabian et al. (2016) Virulence factors enhance Citrobacter rodentium expansion through aerobic respiration. Science 353:1249-53|
|Potts, Rashaun A; Tiffany, Caitlin M; Pakpour, Nazzy et al. (2016) Mast cells and histamine alter intestinal permeability during malaria parasite infection. Immunobiology 221:468-74|
|Costa, Luciana F; Mol, Juliana P S; Silva, Ana Patricia C et al. (2016) Iron acquisition pathways and colonization of the inflamed intestine by Salmonella enterica serovar Typhimurium. Int J Med Microbiol 306:604-610|
|Mooney, Jason P; Lee, Seung-Joo; Lokken, Kristen L et al. (2015) Transient Loss of Protection Afforded by a Live Attenuated Non-typhoidal Salmonella Vaccine in Mice Co-infected with Malaria. PLoS Negl Trop Dis 9:e0004027|
|Mooney, Jason P; Lokken, Kristen L; Byndloss, Mariana X et al. (2015) Inflammation-associated alterations to the intestinal microbiota reduce colonization resistance against non-typhoidal Salmonella during concurrent malaria parasite infection. Sci Rep 5:14603|
|Mooney, J P; Butler, B P; Lokken, K L et al. (2014) The mucosal inflammatory response to non-typhoidal Salmonella in the intestine is blunted by IL-10 during concurrent malaria parasite infection. Mucosal Immunol 7:1302-11|
|Lokken, Kristen L; Mooney, Jason P; Butler, Brian P et al. (2014) Malaria parasite infection compromises control of concurrent systemic non-typhoidal Salmonella infection via IL-10-mediated alteration of myeloid cell function. PLoS Pathog 10:e1004049|
Showing the most recent 10 out of 11 publications