Host Genetic Factors in Resistance and Susceptibility to Tuberculosis Infection and Disease

ABSTRACT

The worldwide public health threat of tuberculosis and the search for novel strategies for preventing and treating disease have focused attention on the interaction between host and pathogen. Despite widespread presence of Mycobacterium tuberculosis, only a relatively small percentage of people exposed to the organism progress to clinical disease. Increasing evidence indicates that host genetic factors influence the outcome of exposure to M. tuberculosis. This evidence is presented here, along with strategies used to identify host genes responsible for resistance/susceptibility in MTB infection. Studies on host genes involved in response to infection by MTB and the relationships between infection and polymorphisms in immune response genes are reviewed. Research on how host genes can influence vaccine responses and the efficacy of drugs or other interventions as well as studies into the relationship of host genes to tuberculosis outcomes may lead to new strategies for prevention and control.

KEYWORDS

Tuberculosis - genetics - infection - disease-resistance

REFERENCES

• 1 Murray C L, Lopez A D. Mortality by cause for eight regions of the world: Global Burden of Disease Study.  Lancet . 1997;  349 1269-1276
• 2 Bloom B R, Small P M. The evolving relation between humans and Mycobacterium tuberculosis N Engl J Med .  1998;  338 677-678
• 3 Qureshi S T, Skamene E, Malo D. Comparative genomics and host resistance against infectious diseases.  Emerg Infect Dis . 1999;  5 36-47
• 3a McNicholl J M, Downer M V, Udhayakumar V. et al . Host-pathogen interactions in emerging and re-emerging infectious diseases: a genomic perspective of tuberculosis, Malaria, human immunodeficiency virus infection, hepatitis B and cholera.  Annu Rev Public Health . 2000;  21 15-46
• 4 Bates J H, Stead W W. The history of tuberculosis as a global epidemic.  Med Clin North Am . 1995;  77 1205-1217
• 5 Greenwood C MT, Fujiwara M, Boothroyd L J. et al . Linkage of tuberculosis to chromosome 2q35 loci, including NRAMP1, in a large Aboriginal Canadian family.  Am J Hum Genet . 2000;  67 405-416
• 6 Stead W W. Genetics and resistance to tuberculosis: could resistance be enhanced by genetic engineering?.  Ann Intern Med . 1992;  116 937-941
• 7 Stead W W, Senner J W, Reddick W T, Lofgren J P. Racial differences in susceptibility to infection by Mycobacterium tuberculosis N Engl J Med .  1990;  322 422-427
• 8 Puffer R R. Familial Susceptibility to Tuberculosis: Its Importance as a Public Health Problem. Cambridge, MA: Harvard University Press 1946
• 9 Kallman F J, Reissner D. Twin studies on the significance of genetic factors in tuberculosis.  Am Rev Tuberc . 1943;  47 549-574
• 10 Simonds B. Tuberculosis in Twins. London: Pittman Medical 1963
• 11 Comstock G W. Tuber twins: a reanalysis of the Prophit survey.  Am Rev Resp Dis . 1978;  117 621-624
• 12 Blackwell J M. Genetics of host resistance and susceptibility to intramacrophage pathogens: a study of multicase families of tuberculosis, leprosy and leishmaniasis in northeastern Brazil.  Int J Parasitology . 1998;  28 21-28
• 13 Lurie M B. Experimental epidemiology of tuberculosis: hereditary resistance to attack by tuberculosis and to the ensuing disease and to the effect of the concentration of tubercle bacilli upon these two phases of resistance.  J Exp Med . 1944;  79 573-589
• 14 Blackwell J M, Black G F, Peacock C S. et al . Immunogenetics of leishmanial and mycobacterial infections: the Belem Family Study.  Int J Trop Parasitol . 1997;  342 1331-1345
• 15 Flynn J L, Goldstein M M, Triebold K J, Koller B, Bloom B R. Major histocompatibility complex class II-restricted T cells are required for resistance to Mycobacterium tuberculosis infection.  Proc Natl Acad Sci USA . 1992;  89 12013-12017
• 16 North R, Izzo A A. Mycobacterial virulence: virulent strains of Mycobacteria tuberculosis have fast in vivo doubling times and are better equipped t resist growth inhibiting functions of macrophages in the presence and absence of specific immunity.  J Exp Med . 1993;  177 1723-1733
• 17 Ladel C H, Blum C, Derne R A, Reifenberg K, Kaufmann S HE. Protective role for gamma/delta T cells and alpha/beta T cells in tuberculosis.  Eur J Immunol . 1995;  25 2877-2881
• 18 Flynn J L, Chan J, Triebold K J. et al . An essential role for interferon gamma in resistance to Mycobacterium tuberculosis infection.  J Exp Med . 1993;  178 2249-2254
• 19 Kamijo R, Le J, Shapiro D. et al . Mice that lack the interferon-gamma receptor have profoundly altered responses to infection with bacillus Calmette-Guérin and subsequent challenge with lipopolysaccharide.  J Exp Med . 1993;  178 1435-1440
• 20 Flynn J K, Goldstein M M, Chan J. et al . Tumor necrosis factor alpha is required in the protective immune response against Mycobacterium tuberculosis in mice.  Immunity . 1995;  2 561-572
• 21 Dalton K, Pitts-Meek S, Keshev S. et al . Multiple effects of immune cell function in mice with disrupted interferon-gamma genes.  Science . 1993;  259 1739-1742
• 22 MacMicking J K, North F, LaCouse R. et al . Identification of nitric oxide synthase as a protective locus against tuberculosis.  Proc Natl Acad Sci USA . 1997;  94 5243-5248
• 23 Bennett S, Leinhardt C, Bah-Sow O. et al . Investigation of environmental and host related risk factors for tuberculosis in Africa. II. Investigation of host genetic factors.  Am J Epidemiol . 2002;  155 1074-1079
• 24 Leinhardt C, Bennett S, Del Prete G. et al . Investigation of environmental and host related risk factors for tuberculosis in Africa. I. Methodological aspects of a combined design.  Am J Epidemiol . 2002;  155 1066-1073
• 25 Brahmajoth V, Pitchappan R M, Kakkanaiah V N. et al . Association of pulmonary tuberculosis and HLAin south India.  Tubercle . 1991;  72 123-132
• 26 Bothamley G H, Beck J S, Schreuder G MT. et al . Association of tuberculosis and M.  tuberculosis-specific antibody levels with HLA. J Infect Dis . 1989;  549-555
• 27 Khomenko A G, Litvinov V I, Chukanova V P, Pospelov L E. Tuberculosis in patients with various HLA phenotypes.  Tubercle . 1990;  71 187-192
• 28 Selvaraj P, Reetha A M, Uma H. et al . Influence of HLA-DR and -DQ phenotypes on tuberculin reactive status in pulmonary tuberculosis patients.  Tuber Lung Dis . 1996;  77 369-373
• 29 Goldfeld A E, Delgado J C, Thim S. et al . Association of an HLA-DQ allele with clinical tuberculosis.  J Am Med Assn . 1998;  279 226-228
• 30 Ravikumar M, Dheenadhayalan V, Rajaram K. et al . Associations of HLA-DRB1 DQB1 and DPB1 alleles with pulmonary tuberculosis in South India.  Tuber Lung Dis . 1999;  79 221-227
• 31 Bellamy R, Ruwende C, Corrah C. et al . Variation in the NRAMP1 gene and susceptibility to tuberculosis in West Africans.  N Engl J Med . 1998;  338 640-644
• 32 Huang J H, Oefner P J, Adi V. et al . Analysis of the NRAMP1 and IFNGR1 genes in women and Mycobacterium avium-intracellulare pulmonary disease.  J Respir Crit Care Med . 1998;  1157 377-381
• 33 Shaw M A, Collins A, Peacock C S. et al . Evidence that genetic susceptibility to Mycobacterium tuberculosis in a Brazilian population is under oligogenic control: linkage study of the candidate genes NRAMP1 and TNFA.  Tuber Lung Dis . 1997;  78 35-45
• 34 Wilkinson R J, Patel P, Llewelyn M. et al . Influence of polymorphism in the genes for the interleukin (IL)-1 receptor antagonist and IL-1 beta on tuberculosis.  J Exp Med . 1999;  189 1863-1874
• 35 Wilkinson R J, Llewelyn M, Toossi Z. et al . Influence of vitamin D deficiency and vitamin D receptor polymorphisms on tuberculosis among Gujarati Asians in west London: a case-control study.  Lancet . 2000;  355 618-621
• 36 Bellamy R, Beyers N, McAdam K W J P. et al . Genetic susceptibility to tuberculosis in Africans: a genome-wide scan.  Proc Natl Acad Sci . 2000;  97 8005-8009
• 37 Levin M, Newport M J, D'Souza S. et al . Familial disseminated atypical mycobacterial infection in childhood: a human mycobacterial susceptibility gene?.  Lancet . 1995;  345 79-83
• 38 Newport M J, Huxley C M, Huston S. et al . Amutation in the interferon gamma-receptor gene, and susceptibility to mycobacterial infection.  N Engl J Med . 1996;  335 1941-1949
• 39 Jouanguy E, Altare F, Lamhamedi S. Interferon gamma receptor deficiency in an infant with fatal bacille Calmette-Guérin infection.  N Engl J Med . 1996;  335 1956-1960
• 40 Dorman S E, Holland S M. Mutation in the signal transducing chain of the interferon gamma receptor and susceptibility to mycobacterial infection.  J Clin Invest . 1998;  101 2364-2369
• 41 Altare F, Lammas D, Revy P. et al . Inherited interleukin-12 deficiency in a child with bacille Calmette-Guérin and Salmonella enteritidis disseminated infection.  J Clin Invest . 1998;  102 2035-2040
• 42 De Jong R, Altare F, Haagen I A. et al . Severe mycobacterial and Salmonella infections in interleukin-12 receptor deficient patients.  Science . 1998;  280 1435-1438
• 43 Sakai T, Matsuoka M, Aoki M, Nosaka K, Mitsuya H. Missense mutation of the interleukin-12 receptor β1 chain-encoding gene is associated with impaired immunity against Mycobacterium avium complexinfection.  Blood . 2001;  97 2688-2694