Infection-related hemolysis and susceptibility to Gram-negative bacterial co-infection

Abstract

Increased susceptibility to co-infection with enteric Gram-negative bacteria, particularly non-typhoidal Salmonella, is reported in malaria and Oroya fever (Bartonella bacilliformis infection), and can lead to increased mortality. Accumulating epidemiological evidence indicates a causal association with risk of bacterial co-infection, rather than just co-incidence of common risk factors. Both malaria and Oroya fever are characterized by hemolysis, and observations in humans and animal models suggest that hemolysis causes the susceptibility to bacterial co-infection. Evidence from animal models implicates hemolysis in the impairment of a variety of host defense mechanisms, including macrophage dysfunction, neutrophil dysfunction, and impairment of adaptive immune responses. One mechanism supported by evidence from animal models and human data, is the induction of heme oxygenase-1 in bone marrow, which impairs the ability of developing neutrophils to mount a competent oxidative burst. As a result, dysfunctional neutrophils become a new niche for replication of intracellular bacteria. Here we critically appraise and summarize the key evidence for mechanisms which may contribute to these very specific combinations of co-infections, and propose interventions to ameliorate this risk.

Impairment of neutrophil oxidative burst in children with sickle cell disease is associated with heme oxygenase-1

“…NTS bacteremia is strongly associated with other diseases which also cause severe hemolysis, particularly malaria and Oroya fever. 33 Hydroxyurea treatment of children with SCD reduces levels of hemolysis, 15 all-cause mortality, 34 and infection-related mortality, 17 suggesting a role for hemolysis in promoting susceptibility to infection in this population. We, and others, have previously shown that hemolysis increases susceptibility to NTS sepsis in a mouse model, 18,35,36 whereas anemia due to blood loss alone does not.…”

Deficiency in reverse cholesterol transport in mice augments sepsis

“…Sepsis and infection are associated with hemolysis and made red blood cell-free hemoglobin released into the circulation (30,31). In clinical study, sepsis caused hemolysis that massive hemoglobin release from red blood cells is a risk factor of septic death (30,32).…”

Malaria-induced remodelling of the bone marrow microenvironment mediates loss of haematopoietic stem cell function

“…berghei infection was chosen as our model as it is a natural rodent infection that includes the skin and livers stages and reproduces several features of human malaria. Malaria is a widespread and severe infection and its effects on HSCs are still poorly understood beyond reports of increased morbidity and infection susceptibility in survivors (Orf & Cunnington, 2015;White, 2018).…”

“…Plasmodium infects and destroys red blood cells, and multiple studies have investigated its impact on erythropoiesis (Dörmer et al, 1983;Maggio-Price, Brookoff & Weiss, 1985;Wickramasinghe et al, 1989;Boehm et al, 2018). It is generally accepted that malaria survivors have compromised haematopoietic and immune function in the short-and long-term (Orf & Cunnington, 2015;White, 2018), and recent studies have begun to link this to alteration in cells of myeloid lineages (Orf & Cunnington, 2015;Mamedov et al, 2018). It is likely that these effects can be traced back to changes in the earliest stages of haematopoiesis, including the HSC compartment.…”