Invasive Non-typhoid Salmonellae Establish Systemic Intracellular Infection in HIV-Infected Adults: An Emerging Disease Pathogenesis

Background. Salmonellae are facultative intracellular pathogens. Non-typhoid salmonellae (NTS) cause self-limiting mucosal disease in immunocompetent adults but invasive, recurrent disease among human immunodeficiency virus (HIV)-infected adults in Africa. The importance of intracellular NTS infection in HIV is unknown. Methods. We performed quantitative pour-plate culture of blood samples obtained during febrile events among 495 Malawian adults on 871 occasions, and NTS were isolated at 158 events. Ninety-eight percent were HIV infected, with a median CD4 count of 67 cells/mu L. Lysis of pour plates and gentamicin exclusion testing were used to investigate the presence of intracellular NTS in blood and bone marrow. Results. Total viable NTS counts in blood were low (1 colony-forming unit [CFU]/mL) but correlated independently with lower CD4 count and with IL-10 and IL-6 levels, especially at recurrence, suggesting failure to clear intracellular infection. Viable NTS load in blood and bone marrow were closely correlated at index events, but NTS were significantly concentrated in bone marrow, compared with blood samples, at recurrences (6 vs 1 CFU/mL), suggesting systemic tissue replication. Both lysis-pour-plating and gentamicin exclusion testing demonstrated intracellular infection with > 1 CFU/cell in both blood and bone marrow specimens. Intracellular bacteria were demonstrated in bone marrow at both index and recurrent events, showing that this is an early and enduring feature of pathogenesis, but intracellular NTS were detected in blood only at index events, particularly in patients with a CD4 count < 50 cells/mu L. Intravascular NTS at recurrence may therefore reflect extracellular "overspill" from an intracellular sanctuary site, following failure of immunological control. Conclusions. Invasive NTS have established a new and emerging pathogenesis in the context of HIV infection in Africa.