Capacity of Mycobacterium avium isolates to grow well or poorly in murine macrophages resides in their ability to induce secretion of tumor necrosis factor

Abstract

The results of this study show that clinical isolates ofMycobacterium avium fail into two categories in terms of their capacity to grow within murine bone marrow-derived macrophage cultures: those that grow progressively and those that are incapable of growing within such cells. Members of the first category were invariably of the smooth-transparent colonial type, while most of the second were of the smooth-domed type. In addition, this paper shows that although all isolates induced tumor necrosis factor (TNF) secretion by host cells to some extent, this production was always delayed in isolates that subsequently grew well in the host cells. This observation, coupled with the demonstration that the growth of the latter isolates was inhibited by the exogenous addition of TNF, leads us to hypothesize that the ability ofa given isolate to somehow avoid host macrophage TNF production early during the course of the infection is a key factor in the pathogenesis of the disease.Infections caused by the Mycobacterium avium complex are the most common causes of bacteremia and disseminated multiorgan bacterial disease in patients with AIDS. M. avium infection is seen clinically in about 25% of patients and is detected upon autopsy in over 50%. To date, treatment of these infections is very difficult because of the high levels of resistance of most M. avium isolates to antimycobacterial drugs (4, 11, 13-15, 17, 25).Isolates of M. avium occur in at least three forms: flat or smooth transparent (SmT), raised or smooth domed (SmD), and rough. All can be observed in cultures of clinical isolates, but SmT is the most prevalent form and is the form most commonly associated with active, disseminated disease (18). There is also an association between colonial morphology and the virulence of the organism, in that recent reports have shown that SmT but not SmD isolates grow well in human monocytes (6,19,24) and that the two forms elicit different cytokine patterns from the infected host cells (19).In the latter report (19), differential cytokine release was reported only for cloned variants derived from a single isolate, so it was unclear whether this represented a general trend. In view of this, in the present study, we examined the ability of a panel of clinical isolates of M. avium to grow in bone marrow-derived murine macrophages. In addition, the cell culture supernatants were harvested at various times and tested for the presence of various cytokines. The results of this study show that while the production of most cytokines tested did not follow any definite trend, there was a marked distinction between the early production of tumor necrosis factor (TNF) by macrophages infected with progressively growing isolates and that by macrophages infected with isolates incapable of growing in these host cells. Our further observation that addition of exogenous TNF was protective regardless of the growth status of the organism leads us to hypothesize that the capacity of a given isolate to * Corresponding author. somehow avoid the product...

Tumour necrosis factor-alpha (TNF-α) in the host resistance to mycobacteria of distinct virulence

“…before the onset of an immune response to the infectious organism) by the avirulent SmOp variant, namely TNF-Q. However, in vitro, neither the avirulent variant nor the more virulent SmTr variants triggered TNF-Q secretion, thus conflicting with the data obtained previously using an ELISA technique to detect secreted cytokine [16]. It was still possible that TNF was being produced and acted in an autocrine loop on the infected macrophages.…”

“…avium (A. Sarmento and R. Appelberg, manuscript in preparation). Thus, the hypothesis raised elsewhere [16], relating avirulence to enhanced TNF triggering, still applies to some situations of Myco. avium infection.…”

“…Thus, virulent strains have different lipoarabinomannan molecules compared with the avirulent H37Ra strain [11,12]. It has been shown that these differences in glycolipid structure are associated with differences in the triggering of TNF-a secretion following infection of the macrophage [11,12,16]. On the basis of these latter observations, it has been speculated that the virulence of a particular mycobacterium depends on its ability to avoid the triggering of TNF secretion when infecting a mononuclear phagocyte.…”

Differential release of tumor necrosis factor-α from murine peritoneal macrophages stimulated with virulent and avirulent species of mycobacteria

“…In this context, differences in the LAM structure have been associated with the ability of the whole organism to survive within macrophages and to generate a productive infection. Further results obtained in an in vitro model of murine macrophage infection by M. avium isolates differing in their ability to grow intracellularly (virulence) suggest that a critical role in host resistance is played by the early phase of TNF-a response [21].…”

Changes in the virulence of Mycobacterium avium after passage through embryonated hens' eggs

“…Studies on the interaction of M. avium isolates from AIDS patients and in vitro-cultured macrophages have shown that strains from patients with active disseminated disease appear to be more virulent and able to survive longer and multiply more rapidly in human monocyte cultures than strains isolated from environmental sources [1,6]. The ability of these M. avium strains to survive correlates strongly with their ability to delay the production of TNF-K [6]. This cytokine may be important in host defenses against mycobacterial pathogens [5,14].…”