HIV gp120 in the Lungs of Antiretroviral Therapy–treated Individuals Impairs Alveolar Macrophage Responses to Pneumococci

Alveolar Macrophage Apoptosis–associated Bacterial Killing Helps Prevent Murine Pneumonia

“…Since we demonstrate a critical role for apoptosis-associated killing in mediating bacterial clearance by macrophages, it follows that upregulation of Mcl-1 influences susceptibility to bacterial pneumonia. The use of a murine model in which we could alter Mcl-1 expression through transgene expression and deliver controlled infections and pharmacological interventions allowed us to confirm the role and mechanisms of this process to an extent not possible with our prior studies in patients (12,13). Our data suggests that susceptibility to bacterial infection can be reversed through therapeutic targeting of the mitochondrial-microbicidal axis or modulation of Mcl-1.…”

“…Although inhibition of apoptosis reduces bacterial killing in these murine models it has not been demonstrated if cellautonomous macrophage apoptosis mediates pathogen clearance (3,11). Recently we have found that a key regulator of macrophage apoptosis during bacterial killing, the anti-apoptotic protein Mcl-1 (11), is upregulated in AM from patients at increased risk of CAP due to chronic obstructive pulmonary disease (COPD) or HIV-1 infection, where it is associated with reduced AM apoptosis and bacterial killing ex vivo (12,13).…”

“…Mcl-1 transgene expression in myeloid cells prolongs macrophage survival but ensures sensitivity to physiological constraints on viability, and that cell numbers remain within the normal range(15).Emerging data in patients at risk of CAP show Mcl-1 upregulation in AM is associated with reduced bacterial killing(12,13). During HIV-1 infection gp120 inhibits Mcl-1 ubiquitination and proteasomal degradation while in COPD transcriptional upregulation is associated with anti-oxidant responses during oxidative stress(12,13) . In our murinemodel over-expression of Mcl-1 using the human transgene converted low dose lung infections, which macrophages normally control (3), into established infections inducing neutrophilic inflammation, phenocopying the susceptibility of patient AM ex vivo.…”

Developing Novel Host-Based Therapies Targeting Microbicidal Responses in Macrophages and Neutrophils to Combat Bacterial Antimicrobial Resistance

“…This capacity can be diminished by interactions with other microorganisms e.g., viruses, environmental factors or co-morbidity, resulting in increased susceptibility to bacterial disease. For example, both HIV-1 infection and chronic obstructive pulmonary disease (COPD) impair alveolar macrophage (AM) killing of pneumococci (16,17). Furthermore, pathogenic bacteria have evolved mechanisms to withstand microbicides, such as antioxidant systems (18).…”

Viruses, Aging, and Chronic Lung Disease

“…In a carefully performed study, Collini and colleagues (pp. 1604-1615) examined the effect of HIV infection on intracellular killing of pneumococci by macrophages (3). They first demonstrated that infecting monocyte-derived macrophages with HIV in vitro resulted in significantly lower late killing of ingested pneumococci through mitochondria-mediated cell apoptosis, without altering initial pneumococci uptake and phagolysosomal killing.…”