Antonio Rothfuchs Project
Mycobacteria cause serious infections in humans, especially the intracellular bacillus Mycobacterium tuberculosis, which is a leading cause of death due to infection. We study the immune response to mycobacteria, especially the initiation of CD4+ T-cell responses. We are also interested in sampling M. tuberculosis from air and in novel therapies against this microorganism.
Dendritic cell responses to mycobacteria
The arrival of mycobacteria in the draining lymph node is necessary for initiating protective, T-cell responses against the bacilli, but this remains poorly understood for both M. tuberculosis and M. bovis Bacille Calmette-Guérin (BCG), the live tuberculosis vaccine. Upon microbial encounter, Dendritic cells at the site of infection become activated and migrate to the draining lymph node where they activate naïve T cells. We are interested in the role played by different Dendritic cells in this process, including the mechanisms by which Dendritic cells mobilize to the lymph node in response to BCG, their ability to ferry BCG to the lymph node, and to trigger the activation CD4+ T cells therein. Understanding the above is critical for deciphering the basis of productive T-cell responses and for advancing our capacity to improve BCG and other vaccines of low-to-modest efficacy that rely on such responses.
Development of a bio-aerosol sampler for M. tuberculosis
We know very little about M. tuberculosis in aerosol droplets, the transmissible form of the pathogen. This is largely due to the lack of adequate detection technology for sampling M. tuberculosis from air. Collecting bacilli from air would advance our understanding of transmission by enabling the subsequent analysis of the transmissible form of the organism. This in turn can be used to deploy tools of impact for intervention of tuberculosis and also to reduce the risk of transmission in high-risk settings. We are developing a sampling device that uses ionization technology to capture airborne mycobacteria. In a uniquely tailored aerobiology chamber, we are testing and refining this device for aerosol sampling of mycobacteria, hoping to create a prototype suitable for field trials.
Antisense-based treatment of tuberculosis
In collaboration with Sarepta Therapeutics, a leader in the field of antisense-based RNA therapeutics, we are evaluating the effect of novel, antisense phosphorodiamidate morpholino oligomers in blocking mycobacterial replication. Similar compounds are also being tested to modulate and consequently improve the immune response to mycobacteria. This technology may lead to the development of new antimicrobials and cell-based therapy against tuberculosis.
Chronic Gastrointestinal Nematode Infection Mutes Immune Responses to Mycobacterial Infection Distal to the Gut.
J. Immunol. 2016 Mar;196(5):2262-71
IL-10 limits parasite burden and protects against fatal myocarditis in a mouse model of Trypanosoma cruzi infection.
J. Immunol. 2012 Jan;188(2):649-60
Intravital imaging reveals limited antigen presentation and T cell effector function in mycobacterial granulomas.
Immunity 2011 May;34(5):807-19
Intranasal Poly-IC treatment exacerbates tuberculosis in mice through the pulmonary recruitment of a pathogen-permissive monocyte/macrophage population.
J. Clin. Invest. 2010 May;120(5):1674-82
In situ IL-12/23p40 production during mycobacterial infection is sustained by CD11bhigh dendritic cells localized in tissue sites distinct from those harboring bacilli.
J. Immunol. 2009 Jun;182(11):6915-25
Macrophage and T cell dynamics during the development and disintegration of mycobacterial granulomas.
Immunity 2008 Feb;28(2):271-84
Dectin-1 interaction with Mycobacterium tuberculosis leads to enhanced IL-12p40 production by splenic dendritic cells.
J. Immunol. 2007 Sep;179(6):3463-71