The phenolic glycolipid of Mycobacterium tuberculosis differentially modulates the early host cytokine response but does not in itself confer hypervirulence

Laboratory of Mycobacterial Immunity and Pathogenesis, TB Center, and Department of Molecular Genetics, Public Health Research Institute Center, University of Medicine and Dentistry of New Jersey 225 Warren St. Newark, NJ 07103 USA; Graduate School of Biomedical Sciences, University of Medicine and Dentistry of New Jersey, 225 Warren St. Newark, NJ 07103 USA; Institut de Pharmacologie et de Biologie Structurale, Département Mécanismes Moléculaires des Infections Mycobactériennes, Université Paul Sabatier de Toulouse, Centre National de la Recherche Scientifique, Toulouse, France; MRC/NHLS/WITS Molecular Mycobacteriology Research Unit, DST/NRF Centre of Excellence for Biomedical TB Research, School of Pathology of the University of the Witwatersrand and the National Health Laboratory Service, Johannesburg, South Africa

^* To whom correspondence should be addressed. Email: kaplangi{at}umdnj.edu.

	Abstract

Mycobacterium tuberculosis (Mtb) possesses a diversity of potential virulence factors including complex branched lipids such as the phenolic glycolipid, PGL-tb. PGL-tb expression by the clinical Mtb isolate HN878 has been associated with a less efficient Th1 response and increased virulence in mice and rabbits. It has been suggested that the W-Beijing family is the only group of Mtb strains with an intact pks1-15 gene, required for the synthesis of PGL-tb, and capable of producing PGL-tb. We have found that some strains with an intact pks1-15 do not produce PGL-tb whilst others may produce a variant of PGL-tb. We examined the early host cytokine response to infection with these strains in vitro to better understand the effect of PGL-tb synthesis on immune responses. In addition, we generated a PGL-tb producing H37Rv in order to determine the effect of PGL-tb production on the host immune response by a strain normally devoid of PGL-tb synthesis during infection. We observed that PGL-tb production by clinical Mtb isolates does not result in a consistent suppression of the host cytokine response when compared to a PGL-tb negative strain. Importantly, while ectopic PGL-tb production by H37Rv suppresses the induction of several pro- and anti-inflammatory cytokines in vitro in human monocytes, it does not lead to increased virulence in infected mice and rabbits. Collectively, our data indicate that whilst PGL-tb may play a role in the immunogenicity and/or virulence of Mtb, it probably acts in concert with other bacterial factors which seem to be dependent on strain background.