Reactivation in tuberculosis a genetic predisposition

For well over a decade it has been believed that innate resistance to mycobacterial infection is controlled by a single gene locus, initially identified in leishmaniasis

FIG. 1. A cartoon representing lesions in the mouse and guinea-pig. In the guinea-pig lymphocytes preferentially occupy the outer mantle, whereas in the mouse these cells invade the epithelioid macrophage fields creating organized rafts of cells.

(Lsi) and salmonellosis (Ity) but now more generally known as Beg, due to the growth of the Montreal strain of Bacillus Calmette-Guerin (BCG) in different mouse strains (Skamene & Forget 1988). More recently, a candidate gene from within this locus, designated Nramp (for 'natural resistance-associated macrophage protein', despite the fact that evidence is slim that it does such a thing) has been identified (Vidal et al 1993).

Despite the fact that Nramp effects are only evident with certain mycobacterial strains (BCG Montreal and Myeobaeterium avium), the inference has gradually developed that all mycobacterial strains are similarly affected, including

M. tuberculosis. That this is incorrect has been clearly shown by North & Medina (1996), who have found that this gene does not influence the growth of

M. tuberculosis.

Even worse, ironically, mouse strains identified as being Bcgr are in fact more susceptible to this infection. We have looked at several such strains in the low dose aerosol infection model, and find that all mouse strains seem to control the infection over the first 40-50 days or so. The infection then appears to become 'chronic' but thereafter the infectious load in the lungs surges (reactivation disease) and the animal dies.

There appears to be a clear hierarchy within strains in terms of this susceptibility. AKR mice undergo reactivation about 100 days post-aerosol, DBA/2 a little later, and CBA between 150 and 200 days. In contrast, Bcgs mice such as C57BL/6 and C57BL/10 do not undergo this event. A comparison of the course of infection in C57BL/6 and DBA/2 mice is shown in Fig. 2.

Histological examination of these two mouse strains has revealed a significant difference between them. In both there is a good macrophage response in the infected lungs, but in the DBA/2 mice there are virtually no lymphocytes present over the initial 40 days. Some lymphocyte infiltration can be seen when the infection then reactivates later, but this appears to be 'too little, too late'.

Erdman

Time in days

FIG. 2. The course of Mycobacterium tuberculosis Erdman infection in C57BL/6 and DBA/2 mouse strains.

Erdman

Time in days

FIG. 2. The course of Mycobacterium tuberculosis Erdman infection in C57BL/6 and DBA/2 mouse strains.

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