CD14 contributes to pulmonary inflammation and mortality during murine tuberculosis

Abstract

Toll-like receptors play an essential role in the innate recognition of micro-organisms by the host. CD14 is one of the extracellular adaptor proteins required for recognition of Gram-negative bacteria and possibly also Mycobacterium tuberculosis. Therefore, we intranasally infected wild-type (WT) and CD14 knock-out (KO) mice with virulent M. tuberculosis H37Rv. We found no differences in bacterial load in the main target organ lung up to 32 weeks after infection. From 20 weeks onward 57% of WT mice succumbed, whereas all CD14 KO mice survived. The improved outcome of CD14 KO mice was accompanied by reduced pulmonary inflammation; lung cell counts and percentage of inflamed lung tissue were reduced in CD14 WT mice. These data suggest that during chronic infection CD14 KO mice are protected from lethality caused by lung tuberculosis because of a reduction of the inflammatory response.

Figure 1

CD14 mice are protected against lethality from infection with Mycobacterium tuberculosis. Wild-type (WT) (n = 14; closed symbols) and CD14 knock-out (KO) mice (n = 14; open symbols) were i.n. infected with 10⁵ CFU of M. tuberculosis and followed for 32 weeks. P < 0·001 for differences between groups.

Figure 2

Unaltered pulmonary bacterial growth in CD14 KO mice. Wild-type (WT) and CD14 knock-out mice (KO) were infected i.n. with 10⁵ CFU of Mycobacterium tuberculosis. One day, 2 and 5 weeks (a) as well as 32 weeks (b) after infection, mice were killed and bacterial loads were determined in lung homogenates. Data are presented as means ± SEM of seven to eight mice per group per time point (early time points) and in 5/14 WT and 14/14 CD14 KO mice that survived the observation period shown in Fig. 1.

Figure 3

CD14 KO mice display reduced lung inflammation at 5 weeks of infection. Representative lung histology of wild-type (WT; a and c) and CD14 knock-out (KO; b and d) mice 2 (a, b) and 5 (c, d) weeks after i.n. infection with 10⁵ CFU of Mycobacterium tuberculosis. The lung sections are representative for seven to eight mice per group per time point. H&E staining, magnification ×5, insert ×20.