Bloodstream infections: mechanisms of pathogenesis and opportunities for intervention

Abstract

Bloodstream infections (BSIs) are common in hospitals, often life-threatening and increasing in prevalence. Microorganisms in the blood are usually rapidly cleared by the immune system and filtering organs but, in some cases, they can cause an acute infection and trigger sepsis, a systemic response to infection that leads to circulatory collapse, multiorgan dysfunction and death. Most BSIs are caused by bacteria, although fungi also contribute to a substantial portion of cases. Escherichia coli, Staphylococcus aureus, coagulase-negative Staphylococcus, Klebsiella pneumoniae and Candida albicans are leading causes of BSIs, although their prevalence depends on patient demographics and geographical region. Each species is equipped with unique factors that aid in the colonization of initial sites and dissemination and survival in the blood, and these factors represent potential opportunities for interventions. As many pathogens become increasingly resistant to antimicrobials, new approaches to diagnose and treat BSIs at all stages of infection are urgently needed. In this Review, we explore the prevalence of major BSI pathogens, prominent mechanisms of BSI pathogenesis, opportunities for prevention and diagnosis, and treatment options.

Fig. 1 |. Primary sites that can seed bloodstream infections and opportunities for prevention and treatment.

Shown are the various primary sites across the body that can seed bloodstream infections. Potential opportunities for the prevention and treatment of bloodstream infection originating at each site are listed.

Fig. 2 |. Pathogens use diverse strategies to infect initial sites and disseminate into the bloodstream.

Bacteria have evolved unique mechanisms to colonize and establish infection across multiple primary niches, and those mechanisms are dependent on species and primary site. a, In the lung, Klebsiella pneumoniae relies on a polysaccharide capsule to resist host defences and iron acquisition by siderophores for replication. Dissemination into the perivascular space and the bloodstream are dependent on siderophore interactions with the host factor hypoxia-inducible factor 1α (HIF1α). For Pseudomonas aeruginosa, lung fitness and dissemination rely on type III and type II secretion systems that inject effector proteins (exotoxins) into host cells to evade innate immunity and permeabilize barriers to the bloodstream. b, In the bladder, Escherichia coli and other urinary tract pathogens use complex adhesion mechanisms (for example, fimbriae) to resist urine flow and invade the bladder epithelium. Leveraging toxin secretion and adhesion mechanisms, E. coli can degrade host barriers and ascend upward into the kidneys, where it can then disseminate into the bloodstream. c, Pathogenic members of the endogenous gut microbiome, like enterococcus, Citrobacter freundii, E. coli and K. pneumoniae can outcompete commensal members (dysbiosis; for example, following antibiotic treatment), which promotes translocation to the bloodstream. d, Colonization of the skin and nares by Staphylococcus aureus is aided by a complex polysaccharide capsule that masks bacterial surface antigens. S. aureus also uses matrix-binding proteins to anchor at these sites. When skin barriers are disrupted through wounds, S. aureus can leverage these immune evasion and matrix-binding strategies to disseminate into the blood. e, Indwelling devices and medical equipment may be contaminated by fungal Candida species, which use highly effective adherence mechanisms to form biofilms. Filamentous Candida albicans are resistant to clearance by neutrophils, perpetuating infection.

Fig. 3 |. Mechanisms of pathogen survival in the bloodstream.

Microorganisms use multiple strategies to survive in the bloodstream and blood-filtering organs. a, Staphylococcus aureus forms foci in blood vessels that function as reservoirs in which bacterial replication occurs and which promote re-seeding of the blood. S. aureus upregulates endothelial expression of the von Willebrand factor and can anchor to endothelial cells using a von Willebrand factor-binding protein. Bacterial effector proteins, including staphylocoagulase, then cause additional aggregation, which leads to the formation of clots within vessels. b, Gram-negative species like Escherichia coli, Klebsiella pneumoniae, Serratia marcescens and Citrobacter freundii rely on metabolic flexibility to survive in this microenvironment. Central carbon metabolism is required to survive in the bloodstream, and separate species have differential requirements for the metabolism of various amino acids to survive in this niche. c, All pathogens that cause bloodstream infections must also evade killing by immune mechanisms in the blood, such as complement deposition and the formation of a membrane attack complex, or targeting by antimicrobial peptides. Many microorganisms use an extensive polysaccharide capsule to evade membrane attack complex formation on the surface, cleave complement with proteases or modify the charge of the lipopolysaccharide (LPS) to repel charged antimicrobial peptides. d, Polysaccharide capsule can also influence the interactions with different immune subsets. Unencapsulated K. pneumoniae and capsule types that cannot prevent phagocytosis are readily cleared by tissue-resident Kupffer cells in the liver. K2 capsule-type K. pneumoniae can replicate within Kupffer cells, which leads to host cell death and the formation of abscesses, in which the bacteria can further replicate and seed the bloodstream.