title: Clade-specific virulence patterns of Mycobacterium tuberculosis complex strains in human primary macrophages and aerogenically infected mice.
abstract: In infection experiments with genetically distinct Mycobacterium tuberculosis complex (MTBC) strains, we identified clade-specific virulence patterns in human primary macrophages and in mice infected by the aerosol route, both reflecting relevant model systems. Exclusively human-adapted M. tuberculosis lineages, also termed clade I, comprising "modern" lineages, such as Beijing and Euro-American Haarlem strains, showed a significantly enhanced capability to grow compared to that of clade II strains, which include "ancient" lineages, such as, e.g., East African Indian or M. africanum strains. However, a simple correlation of inflammatory response profiles with strain virulence was not apparent. Overall, our data reveal three different pathogenic profiles: (i) strains of the Beijing lineage are characterized by low uptake, low cytokine induction, and a high replicative potential, (ii) strains of the Haarlem lineage by high uptake, high cytokine induction, and high growth rates, and (iii) EAI strains by low uptake, low cytokine induction, and a low replicative potential. Our findings have significant implications for our understanding of host-pathogen interaction and factors that modulate the outcomes of infections. Future studies addressing the underlying mechanisms and clinical implications need to take into account the diversity of both the pathogen and the host.
  
  
  OBJECTIVE
  Clinical strains of the Mycobacterium tuberculosis complex (MTBC) are genetically more diverse than previously anticipated. Our analysis of mycobacterial growth characteristics in primary human macrophages and aerogenically infected mice shows that the MTBC genetic differences translate into pathogenic differences in the interaction with the host. Our study reveals for the first time that "TB is not TB," if put in plain terms. We are convinced that it is very unlikely that a single molecular mechanism may explain the observed effects. Our study refutes the hypothesis that there is a simple correlation between cytokine induction as a single functional parameter of host interaction and mycobacterial virulence. Instead, careful consideration of strain- and lineage-specific characteristics must guide our attempts to decipher what determines the pathological potential and thus the outcomes of infection with MTBC, one of the most important human pathogens.
authors.affiliation: Microbial Interface Biology, Center for Clinical Studies, Research Center Borstel, Borstel, Germany. nreiling@fz-borstel.de
authors.forename: Norbert
authors.initials: N
authors.lastname: Reiling
authors.forename: Susanne
authors.initials: S
authors.lastname: Homolka
authors.forename: Kerstin
authors.initials: K
authors.lastname: Walter
authors.forename: Julius
authors.initials: J
authors.lastname: Brandenburg
authors.forename: Lisa
authors.initials: L
authors.lastname: Niwinski
authors.forename: Martin
authors.initials: M
authors.lastname: Ernst
authors.forename: Christian
authors.initials: C
authors.lastname: Herzmann
authors.forename: Christoph
authors.initials: C
authors.lastname: Lange
authors.forename: Roland
authors.initials: R
authors.lastname: Diel
authors.forename: Stefan
authors.initials: S
authors.lastname: Ehlers
authors.forename: Stefan
authors.initials: S
authors.lastname: Niemann
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D054884:Host-Pathogen Interactions; D006801:Humans; D008264:Macrophages / Q000382:microbiology*; D051379:Mice; D009169:Mycobacterium tuberculosis / Q000145:classification / Q000235:genetics* / Q000302:isolation & purification / Q000472:pathogenicity*; D014397:Tuberculosis, Pulmonary / Q000382:microbiology* / Q000473:pathology*; D014774:Virulence; D037521:Virulence Factors / Q000235:genetics* / Q000378:metabolism*
chemical_list: D016207:Cytokines; D037521:Virulence Factors
references.citation: Annu Rev Immunol. 2004;22:599-623
references.pmid: 15032590
references.citation: PLoS Pathog. 2011 Mar;7(3):e1001307
references.pmid: 21408618
references.citation: PLoS One. 2009 Oct 12;4(10):e7407
references.pmid: 19823582
references.citation: PLoS One. 2013;8(1):e55254
references.pmid: 23383127
references.citation: PLoS One. 2010 Oct 25;5(10):e13594
references.pmid: 21049036
references.citation: Lancet Infect Dis. 2007 May;7(5):328-37
references.pmid: 17448936
references.citation: Infect Immun. 2004 Sep;72(9):5511-4
references.pmid: 15322056
references.citation: Proc Natl Acad Sci U S A. 2002 Mar 19;99(6):3684-9
references.pmid: 11891304
references.citation: PLoS Pathog. 2009 Sep;5(9):e1000577
references.pmid: 19750224
references.citation: PLoS Pathog. 2008 Sep 19;4(9):e1000160
references.pmid: 18802459
references.citation: Proc Natl Acad Sci U S A. 2006 Feb 21;103(8):2869-73
references.pmid: 16477032
references.citation: J Immunol. 2001 Sep 15;167(6):3339-45
references.pmid: 11544323
references.citation: Clin Vaccine Immunol. 2010 Jul;17(7):1094-103
references.pmid: 20463103
references.citation: J Clin Microbiol. 2007 Feb;45(2):409-14
references.pmid: 17166963
references.citation: Cell Host Microbe. 2008 Feb 14;3(2):97-103
references.pmid: 18312844
references.citation: Respir Res. 2005 Apr 14;6:35
references.pmid: 15831092
references.citation: PLoS One. 2012;7(8):e43170
references.pmid: 22916219
references.citation: PLoS Pathog. 2008 Mar 28;4(3):e1000034
references.pmid: 18369480
references.citation: Trans R Soc Trop Med Hyg. 2009 Jun;103(6):581-7
references.pmid: 19375139
references.citation: Nature. 2004 Sep 2;431(7004):84-7
references.pmid: 15343336
references.citation: PLoS Pathog. 2010 Jul 08;6(7):e1000988
references.pmid: 20628579
references.citation: Pneumologie. 2004 May;58(5):344-56
references.pmid: 15162262
references.citation: PLoS One. 2013 Apr 16;8(4):e61358
references.pmid: 23613838
references.citation: J Immunol. 2002 Oct 1;169(7):3480-4
references.pmid: 12244136
references.citation: Hum Mol Genet. 2008 Apr 1;17(7):1052-60
references.pmid: 18174194
references.citation: Annu Rev Immunol. 2001;19:93-129
references.pmid: 11244032
references.citation: J Infect Dis. 2006 May 1;193(9):1279-86
references.pmid: 16586366
references.citation: Clin Exp Immunol. 2003 Jul;133(1):30-7
references.pmid: 12823275
references.citation: J Clin Microbiol. 2007 May;45(5):1483-90
references.pmid: 17360841
references.citation: J Infect Dis. 2008 Oct 1;198(7):1037-43
references.pmid: 18702608
references.citation: PLoS One. 2011;6(6):e20908
references.pmid: 21695215
references.citation: Nat Genet. 2010 Jun;42(6):498-503
references.pmid: 20495566
references.citation: PLoS Biol. 2008 Dec 16;6(12):e311
references.pmid: 19090620