Perspective: a molecular approach to tuberculosis control-- an idea that might work.

In any large outbreak of tuberculosis, there are some individever, no such deletion has been found among persons from Africa or Asia, where HIV is a scourge. Study subjects uals who appear to have been significantly exposed but who remain healthy and tuberculin skin test–negative. Is it simply included persons with continued risky sexual behavior and well-defined cohorts of hemophiliacs receiving blood prodluck that they are spared? Or could some have an unusually great resistance to the infection? If so, might not this be genetiucts from HIV-1 – positive donors [3]. cally mediated? In 1990 we happened upon evidence of a significant disparity I have been intrigued by this possibility since 1957, when in susceptibility to M. tuberculosis among equally exposed I read a negative tuberculin skin test on the arm of a healthy black and white nursing home residents and in three outbreaks nurse on her retirement at age 65. How could this happen in in younger persons in two prisons [4]. In two papers on the a person who had been a ‘‘hands-on’’ nurse on a tuberculosis genetics of resistance to tuberculosis, I have suggested a plausisurgical ward during the 1940s and 1950s? For 30 years, she ble way in which such a racial discrepancy may have developed was exposed daily to the most infectious cases of tuberculosis [5, 6]. I proposed that genetic engineers compare persons apin patients undergoing thoracoplasty or pulmonary resection. pearing to have great resistance to initial infection by M. tuberCertainly, neither luck nor anergy could explain her negative culosis with persons who not only are infected but who have skin test. In the ensuing 40 years that I have studied tuberculodeveloped the actual disease. The challenge would be to idensis, I have observed a number of similar, albeit less dramatic, tify persons known to have great and repeated exposures to instances. tuberculosis while remaining healthy and skin test–negative. I The most widely used vaccine in the history of medicine is now can suggest a way to garner a sizable group of such bacille Calmette-Guerin (BCG), an attenuated form of Mycopersons. bacterium bovis. However, it is generally conceded to do little Catanzaro [7] demonstrated the very considerable risk of to prevent tuberculosis. In contrast to smallpox, which disapinfection by M. tuberculosis among bronchoscopists. The same peared with worldwide vaccination, the incidence and prevais true among anatomic pathologists in large general hospitals lence of tuberculosis are increasing throughout the Third World and medical examiners in big cities. We reported the infection in the face of BCG’s long-standing and wide use. of 5 of 5 tuberculin-negative persons performing or attending As molecular biologists began to identify the genetic basis the necropsy of a man who had died of miliary tuberculosis for various diseases, I began to envisage their finding a gene [8]. Within 8 weeks, 2 of the 5 had positive sputum cultures associated with great resistance to tuberculosis. Might such a that showed a restriction fragment length polymorphism pattern gene make a protein to block the entry of Mycobacterium identical with that of the organisms from the patient. Anyone tuberculosis into human cells? If so, could it be exploited as who remains healthy and tuberculin skin test–negative after 5 a preventive? We all know that yesterday’s science fiction is years of such high-exposure work before the advent of modern today’s reality. environmental controls stands a very great chance of being My clinical conviction was greatly strengthened by redifficult to infect with M. tuberculosis. The genomes of such cent reports showing complete resistance to our most persons should be searched for differences from genomes of dreaded infection, that due to human immunodeficiency persons who are not only skin test–positive but who have virus (HIV). In 17% – 20% of Caucasians, there is a 32-bp clinical tuberculosis. deletion in the CCR5 gene associated with complete innate It now seems likely that the idea of a single gene conferring resistance to HIV infection [1, 2]. Heterozygous persons resistance to any pathogen is simplistic. However, it seems show greatly slowed progression of the infection [3]. Howpossible that identification of a gene or combination of genes conferring primary resistance to tuberculosis might lead to development of a more effective method of prevention. This could have the advantage of not producing tuberculin sensitivity in Received 13 April 1997; revised 8 May 1997. the recipient and thus would not interfere with use of the skin Reprints or correspondence: Dr. William W. Stead, Tuberculosis Program, Mail slot 45, Arkansas Dept. of Health, 4815 W. Markham St., Little Rock, test to identify tuberculin reactors who would benefit from AR 72205-3867. prophylactic chemotherapy. One can envisage this being of The Journal of Infectious Diseases 1997;176:547–8 value in preventing tuberculous infection in persons at risk in q 1997 by The University of Chicago. All rights reserved. 0022–1899/97/7603–0001$02.00 hospitals, nursing homes, homeless shelters, and prisons, as