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Host-Microbe Interactions

Research Summary

André Báfica is studying the mechanisms by which the immune system senses infectious agents.

The concept of pathogen-associated molecular patterns (PAMPs) was proposed by Charles Janeway (HHMI alumnus, Yale University) and his colleagues in 1989. Expressed in pathogens, but not by the host, PAMPs are structures—such as lipids, proteins, nucleic acids, and sugars—that are sensed by innate pattern recognition receptors (PRRs). PAMP-host interactions induce inflammatory responses involving a complex cascade of mediators, including tumor necrosis factor (TNF), interleukin-12 (IL-12), and IL-10.

During the past decade, the innate immunity field has been dedicated to understanding how the PAMP-PRR axis modulates complex signaling pathways to generate potent adaptive immune responses. Today we know, for example, that pathogen-derived molecules may be the most potent vaccine adjuvant factors, and this basic understanding has been utilized in new vaccines. Pathways involved in pathogen recognition by antigen-presenting cells (APCs) orchestrate the immune system to eliminate infection. Receptors expressed on APCs, as well as pathogen-derived factors, are thought to be critical to the outcome of optimal host immunity.

My lab has focused on chronic infections caused by parasite as well as bacterial pathogens, which produce a number of molecules found to control immune responses. Several PRRs of the innate immune system have been demonstrated to sense one of the most successful human pathogens, Mycobacterium tuberculosis. In contrast, mycobacteria-secreted proteins may impact immune responses and influence protection in vivo.

Our long-term goal is to elucidate the mechanisms by which secreted proteins from M. tuberculosis regulate immune responses in humans. My interest in this subject stems from my previous finding that innate immune receptors (PRRs) cooperate to sense a number of factors produced by M. tuberculosis, influencing host resistance against this pathogen. In mycobacteria, a number of PAMPs have been described and lipid moieties (such as PIM, LAM, and 19-kDa lipoprotein), sugar structures (such as mannose), and nucleic acids (e.g., DNA) trigger PRR-dependent responses. In addition to lipid and carbohydrate molecules, ESAT-6, a previously characterized protein secreted by M. tuberculosis, has recently been shown to trigger Toll-like receptor 2, an example of PRR signaling, suggesting that mycobacterial protein antigens modulate host innate immune responses.

To date, however, few protein molecules serving as PAMPs have been described. This is particularly interesting because a protein PAMP can both stimulate the innate immune system by means of PRR activation and be recognized as an antigen by T and B lymphocytes to induce adaptive immunity. Consequently, protein PAMPs known to be immunodominant antigens may be ideal candidates for vaccine development. Therefore, discovery of mycobacterial antigens that have characteristics of both PAMPs and antigens is a critical step to generate novel adjuvant/vaccine candidates against tuberculosis. Our goal is to define and characterize molecules expressed by the causative agent of tuberculosis, M. tuberculosis, that may be utilized as candidate antigens for vaccines and surrogate biomarkers.

Among possible mycobacteria-associated patterns, carbohydrates, which participate in a series of biochemical processes and may be recognized by host PRRs, are important codifiers. We have generated a nonredundant lectin database in an attempt to identify lectin (sugar-binding protein) domains from M. tuberculosis. Following bioinformatics analysis, we identified sMTL-13, a 13-kDa ricin-like lectin from M. tuberculosis. Several experiments indicate that sMTL-13 induces cytokine expression by macrophages, and it is recognized by immunoglobulin G (IgG) present in the serum of patients with active tuberculosis. These data prompted us to study whether sMTL-13 is a protein mycobacteria-derived molecular pattern and the mechanisms by which APCs sense sMTL-13.

We are also testing whether sMTL-13 participates in physiological processes such as cell wall formation. To do so, we have generated M. tuberculosis–deficient mutants to perform a detailed characterization of both microbe-host interactions and pathogen physiology. (Our collaborators on these projects include Lee Riley, Alan Sher, Carl Feng, Sérgio C. Oliveira, Daniel Mansur, and Henrique Teixeira.)

Grants from the National Institutes of Health and the National Council for Scientific and Technological Development (CNPq) provided partial support for these projects.

As of January 17, 2012