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

Melita A. Gordon; Anstead M.K. Kankwatira; Gershom Mwafulirwa; Amanda L. Walsh; Mark J. Hopkins; Christopher Parry; E. Brian Faragher; Eduard E. Zijlstra; Robert S. Heyderman; Malcolm E. Molyneux

doi:10.1086/651080

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

Melita A. Gordon, Anstead M.K. Kankwatira, Gershom Mwafulirwa, Amanda L. Walsh, Mark J. Hopkins, Christopher Parry, E. Brian Faragher, Eduard E. Zijlstra, Robert S. Heyderman, Malcolm E. Molyneux

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Abstract

Background. Salmonellae are facultative intracellular pathogens. Non-typhoid salmonellae (NTS) cause selflimiting

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/mL. 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 11 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/mL. 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.

Original language	English
Pages (from-to)	953-962
Number of pages	10
Journal	Clinical Infectious Diseases
Volume	50
Issue number	7
DOIs	https://doi.org/10.1086/651080
Publication status	Published - 1 Apr 2010
Externally published	Yes

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Gordon, M. A., Kankwatira, A. M. K., Mwafulirwa, G., Walsh, A. L., Hopkins, M. J., Parry, C., Brian Faragher, E., Zijlstra, E. E., Heyderman, R. S., & Molyneux, M. E. (2010). Invasive Non-typhoid Salmonellae Establish Systemic Intracellular Infection in HIV-Infected Adults: An Emerging Disease Pathogenesis. Clinical Infectious Diseases, 50(7), 953-962. https://doi.org/10.1086/651080

@article{d0e7946941814d16a9194236c0f7105a,

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

abstract = "Background. Salmonellae are facultative intracellular pathogens. Non-typhoid salmonellae (NTS) cause selflimitingmucosal disease in immunocompetent adults but invasive, recurrent disease among human immunodeficiencyvirus (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 among495 Malawian adults on 871 occasions, and NTS were isolated at 158 events. Ninety-eight percent were HIVinfected, with a median CD4 count of 67 cells/mL. Lysis of pour plates and gentamicin exclusion testing were usedto 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 independentlywith lower CD4 count and with IL-10 and IL-6 levels, especially at recurrence, suggesting failure toclear 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 1CFU/mL), suggesting systemic tissue replication. Both lysis-pour-plating and gentamicin exclusion testing demonstratedintracellular infection with 11 CFU/cell in both blood and bone marrow specimens. Intracellular bacteriawere demonstrated in bone marrow at both index and recurrent events, showing that this is an early and enduringfeature of pathogenesis, but intracellular NTS were detected in blood only at index events, particularly in patientswith a CD4 count !50 cells/mL. Intravascular NTS at recurrence may therefore reflect extracellular “overspill” froman 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.",

author = "Gordon, \{Melita A.\} and Kankwatira, \{Anstead M.K.\} and Gershom Mwafulirwa and Walsh, \{Amanda L.\} and Hopkins, \{Mark J.\} and Christopher Parry and \{Brian Faragher\}, E. and Zijlstra, \{Eduard E.\} and Heyderman, \{Robert S.\} and Molyneux, \{Malcolm E.\}",

year = "2010",

month = apr,

day = "1",

doi = "10.1086/651080",

language = "English",

volume = "50",

pages = "953--962",

journal = "Clinical Infectious Diseases",

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}

Gordon, MA, Kankwatira, AMK, Mwafulirwa, G, Walsh, AL, Hopkins, MJ, Parry, C, Brian Faragher, E, Zijlstra, EE, Heyderman, RS & Molyneux, ME 2010, 'Invasive Non-typhoid Salmonellae Establish Systemic Intracellular Infection in HIV-Infected Adults: An Emerging Disease Pathogenesis', Clinical Infectious Diseases, vol. 50, no. 7, pp. 953-962. https://doi.org/10.1086/651080

TY - JOUR

T1 - Invasive Non-typhoid Salmonellae Establish Systemic Intracellular Infection in HIV-Infected Adults: An Emerging Disease Pathogenesis

AU - Gordon, Melita A.

AU - Kankwatira, Anstead M.K.

AU - Mwafulirwa, Gershom

AU - Walsh, Amanda L.

AU - Hopkins, Mark J.

AU - Parry, Christopher

AU - Brian Faragher, E.

AU - Zijlstra, Eduard E.

AU - Heyderman, Robert S.

AU - Molyneux, Malcolm E.

PY - 2010/4/1

Y1 - 2010/4/1

N2 - Background. Salmonellae are facultative intracellular pathogens. Non-typhoid salmonellae (NTS) cause selflimitingmucosal disease in immunocompetent adults but invasive, recurrent disease among human immunodeficiencyvirus (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 among495 Malawian adults on 871 occasions, and NTS were isolated at 158 events. Ninety-eight percent were HIVinfected, with a median CD4 count of 67 cells/mL. Lysis of pour plates and gentamicin exclusion testing were usedto 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 independentlywith lower CD4 count and with IL-10 and IL-6 levels, especially at recurrence, suggesting failure toclear 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 1CFU/mL), suggesting systemic tissue replication. Both lysis-pour-plating and gentamicin exclusion testing demonstratedintracellular infection with 11 CFU/cell in both blood and bone marrow specimens. Intracellular bacteriawere demonstrated in bone marrow at both index and recurrent events, showing that this is an early and enduringfeature of pathogenesis, but intracellular NTS were detected in blood only at index events, particularly in patientswith a CD4 count !50 cells/mL. Intravascular NTS at recurrence may therefore reflect extracellular “overspill” froman 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.

AB - Background. Salmonellae are facultative intracellular pathogens. Non-typhoid salmonellae (NTS) cause selflimitingmucosal disease in immunocompetent adults but invasive, recurrent disease among human immunodeficiencyvirus (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 among495 Malawian adults on 871 occasions, and NTS were isolated at 158 events. Ninety-eight percent were HIVinfected, with a median CD4 count of 67 cells/mL. Lysis of pour plates and gentamicin exclusion testing were usedto 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 independentlywith lower CD4 count and with IL-10 and IL-6 levels, especially at recurrence, suggesting failure toclear 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 1CFU/mL), suggesting systemic tissue replication. Both lysis-pour-plating and gentamicin exclusion testing demonstratedintracellular infection with 11 CFU/cell in both blood and bone marrow specimens. Intracellular bacteriawere demonstrated in bone marrow at both index and recurrent events, showing that this is an early and enduringfeature of pathogenesis, but intracellular NTS were detected in blood only at index events, particularly in patientswith a CD4 count !50 cells/mL. Intravascular NTS at recurrence may therefore reflect extracellular “overspill” froman 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.

U2 - 10.1086/651080

DO - 10.1086/651080

M3 - Article

SN - 1058-4838

VL - 50

SP - 953

EP - 962

JO - Clinical Infectious Diseases

JF - Clinical Infectious Diseases

IS - 7

ER -

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

Abstract

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