Microbial pathogenisity in tuberculosis

Arbete i dragskåp med tuberkulos-prover
Susmita K. Singh and Robert Blomgran preparing to analyze tuberculosis samples.

How does co-infection modulate the innate immune response during TB infection?

Konfokalmikroskop-bild
One of the main reasons why tuberculosis (TB) is increasing worldwide is that many TB patients are also co-infected with HIV. The synergistic effects of TB and acquired immunodeficiency syndrome (AIDS) is a major global health concern, illustrated by the fact that the risk of developing active TB is one in ten in a lifetime in TB-infected persons, and one in ten per year in HIV co-infected persons (1)
 
The geographical distribution of intestinal helminthes overlap with that of TB, also affecting global health and exacerbate disease in patients with TB (2).
 
Most research efforts have been assigned to studying the effect of the causative bacteria M. tuberculosis (Mtb), HIV, or helminthes separately and in the context of the adaptive immune response.
 
Our research focuses on the beneficial role of innate immune cells and their cooperation for the control of Mtb during simultaneous co-infection. The focus is on innate immune cells such as macrophages, neutrophils, and dendritic cells and how intrinsic antimicrobial functions of these cells can be enhanced to suppress Mtb, and how co-infections modulate these responses.
 
One hypothesis is that interactive functions of innate cells are crucial for the control of TB in patients with chronic infections.

Main projects

  1. Characterize how co-infection with HIV affects functions in Mtb-infected macrophages. Investigating the ability of HIV to manipulate handling and killing of intracellular Mtb, focusing on cell signaling, phagolysosome fusion and manipulation of the activation status of macrophages.
  2. Characterize the effect of Mtb-HIV co-infection in immature dendritic cells. Focusing on the effect of HIV on dendritic cell-activation, maturation, and cellular functions involved during Mtb infection.
  3. The effect on innate immune cell functions by other co-infections. Although the primary focus is TB and co-infection with HIV, studies are currently undertaken to investigate the effect of helminthes on the innate immune cell capacity to elicit proper response to Mtb.
  4. Characterize how the cells of innate immunity interact in order to control Mtb during co-infection. We have shown that interaction between innate immune cells play an important role in the control of TB. Apoptotic neutrophils containing Mtb was seen to trigger a strong pro-inflammatory response in macrophages, necessary to control intracellular replication of the bacterium. The use of in vivo models has recently confirmed the role of apoptosis and neutrophils in the cellular cross-talk and immune activation during TB-infections (3, 4). Now the challenge is to investigate whether this cross-talk between innate immune cells is efficacious also for overcoming HIV-induced (or helminthes-induced) suppression on cellular functions, and to decipher these mechanisms.>

References

Barnes, P. F., A. B. Bloch, P. T. Davidson, and D. E. Snider, Jr. 1991.
Tuberculosis in patients with human immunodeficiency virus infection.
The New England journal of medicine 324(23):1644-1650.

Salgame, P., G.S. Yap, and W.C. Gause 2013.
Effect of helminth-induced immunity on infections with microbial pathogens.
Nat Immunol. 14(11):1118-1126.

Blomgran, R., and J. D. Ernst. 2011.
Lung neutrophils facilitate activation of naive antigen-specific CD4+ T cells during Mycobacterium tuberculosis infection.
Journal of immunology. 186(12):7110-7119.

Blomgran, R., L. Desvignes, V. Briken, and J.D. Ernst. 2012.
Mycobacterium tuberculosis inhibits neutrophil apoptosis, leading to delayed activation of naive CD4 T cells.
Cell host & microbe 11(1):81-90.

Publications
Show/Hide content

2019

Show/Hide content

Staff
Show/Hide content

Related content
Show/Hide content