Both Hemolytic Anemia and Malaria Parasite-Specific Factors Increase Susceptibility to Nontyphoidal Salmonella enterica Serovar Typhimurium Infection in Mice

• Published in: Infection and Immunity Vol. 78; no. 4; pp. 1520 - 1527
• Main Authors: Roux, Christelle M, Butler, Brian P, Chau, Jennifer Y, Paixao, Tatiane A, Cheung, Kong Wai, Santos, Renato L, Luckhart, Shirley, Tsolis, Renée M
• Format: Journal Article
• Language: English
• Published: Washington, DC American Society for Microbiology 01.04.2010; American Society for Microbiology (ASM)
• Subjects: Anemia, Hemolytic; Anemia, Hemolytic - complications; animal models; Animals; Bacterial diseases; Bacterial diseases of the digestive system and abdomen; Bacterial Infections; Bacteriology; Biological and medical sciences; blood; blood serum; Colony Count, Microbial; complications; Disease Models, Animal; Disease Susceptibility; Female; Fundamental and applied biological sciences. Psychology; hemolysis; hemolytic anemia; Human bacterial diseases; Human protozoal diseases; Humans; immunology; Infectious diseases; Interleukin-12; Interleukin-12 - blood; liver; Liver - microbiology; macrophages; Malaria; Malaria - complications; Medical sciences; Mice; Microbiology; Miscellaneous; mixed infection; Parasitic diseases; pathogenicity; Plasmodium yoelii; Plasmodium yoelii - pathogenicity; Plasmodium yoelii nigeriensis; Protozoal diseases; risk factors; Salmonella Infections, Animal; Salmonella Infections, Animal - immunology; Salmonella Infections, Animal - microbiology; Salmonella Typhimurium; Salmonella typhimurium - immunology; Salmonella typhimurium - pathogenicity; serotypes; spleen; Spleen - microbiology; Protozoal disease; Malaria; Rodentia; Hemopathy; Parasitosis; Immunity; Salmonella typhimurium; Infection; Vertebrata; Sensitivity; Mammalia; Hemolytic anemia; Mouse; Bacteriosis; Bacteria; Salmonellosis; Enterobacteriaceae
• ISSN: 0019-9567; 1098-5522; 1098-5522
• DOI: 10.1128/IAI.00887-09

Severe pediatric malaria is an important risk factor for developing disseminated infections with nontyphoidal Salmonella serotypes (NTS). While recent animal studies on this subject are lacking, early work suggests that an increased risk for developing systemic NTS infection during malaria is caused by hemolytic anemia, which leads to reduced macrophage microbicidal activity. Here we established a model for oral Salmonella enterica serotype Typhimurium challenge in mice infected with Plasmodium yoelii nigeriensis. Initial characterization of this model showed that 5 days after coinoculation, P. yoelii nigeriensis infection increased the recovery of S. Typhimurium from liver and spleen by approximately 1,000-fold. The increased bacterial burden could be only partially recapitulated by antibody-mediated hemolysis, which increased the recovery of S. Typhimurium from liver and spleen by 10-fold. These data suggested that both hemolysis and P. yoelii nigeriensis-specific factors contributed to the increased susceptibility to S. Typhimurium. The mechanism by which hemolysis impaired resistance to S. Typhimurium was further investigated. In vitro, S. Typhimurium was recovered 24 h after infection of hemophagocytic macrophages in 2-fold-higher numbers than after infection of mock-treated macrophages, making it unlikely that reduced macrophage microbicidal activity was solely responsible for hemolysis-induced immunosuppression during malaria. Infection with P. yoelii nigeriensis, but not antibody-mediated hemolysis, reduced serum levels of interleukin-12p70 (IL-12p70) in response to S. Typhimurium challenge. Collectively, studies establishing a mouse model for this coinfection suggest that multiple distinct malaria-induced immune defects contribute to increased susceptibility to S. Typhimurium.