Procession to pediatric bacteremia and sepsis: covert operations and failures in diplomacy

Abstract

Despite advances in diagnosis and treatment, bacterial sepsis remains a major cause of pediatric morbidity and mortality, particularly among neonates, the critically ill, and the growing immunocompromised patient population. Sepsis is the end point of a complex and dynamic series of events in which both host and microbial factors drive high morbidity and potentially lethal physiologic alterations. In this article we provide a succinct overview of the events that lead to pediatric bloodstream infections (BSIs) and sepsis, with a focus on the molecular mechanisms used by bacteria to subvert host barriers and local immunity to gain access to and persist within the systemic circulation. In the events preceding and during BSI and sepsis, Gram-positive and Gram-negative pathogens use a battery of factors for translocation, inhibition of immunity, molecular mimicry, intracellular survival, and nutrient scavenging. Gaps in understanding the molecular pathogenesis of bacterial BSIs and sepsis are highlighted as opportunities to identify and develop new therapeutics.

Figure 1. Bacterial-host interactions during the progression of BSI and sepsis

Panel (A) depicts the pathogenic steps that bacteria must undergo to gain access to and persist within the circulatory system, with pathogen interaction with the host innate and adaptive immune system highlighted. Bacteria often initiate the infection process through colonization of the mucosal surface of the intestine, respiratory tract, or urogenital tract (1), after which, bacteria can traverse the epithelial barrier transcellularly, paracellularly, or as intracellular passengers within granulocytes and mononuclear cells (2). Bacteria must then survive in connective tissues (3), cross the endothelial-blood barrier (4), and survive and persist in the circulatory system (5). Bacterial pathogens have evolved multiple mechanisms to avoid clearance by professional phagocytes, like neutrophils and macrophages, by synthesizing the immunosuppressant nucleoside adenosine, assembling sialic acid or haluronic acid capsules to inhibit phagocytosis and dampen the immune response, limiting deposition of complement factor C3b, and coating themselves with incorrectly-oriented IgG antibody to limit opsonophagocytosis. Bacteria have evolved mechanisms to survive within the systemic circulation by scavaging metals, eg. iron, with high-affinity molecules called siderophores. Finally, bacterial pathogens can exit the circulatory system, causing end-organ dissemination and/or failure (6). Panel (B) illustrates host mechanisms employed to contain infection, including phagocytosis and innate pathogen-associated molecular pattern (PAMP) recognition through the Toll-like receptors (TLR) and intracellular nucleotide oligomerization domain/caspase recruitment domain (NOD/CARD) proteins, such as Nod1/2. Phagocytosis and lysosomal fusion are typically part of a unified pathway to clear pathogens, but bacteria have evolved countermeasures to avoid being killed. Panel (C) demonstrates antigen-dependent (MHC presentation) and –independent (superantigen) activation of the adaptive immune system by phagosome-contained and cytoplasmic bacteria. Successful activation of the adaptive immune branch is a key step in bacterial clearance; however, non-antigen-dependent activation of T helper cells via bacterial superantigens elaborates a destructive cascade of cytokine release and non-specific T cell proliferation. Antigens from intracellular pathogens are processed through the proteasome into peptides, transported into the endoplamic reticulum (ER), captured by MHCI molecules, and presented to CD8+ T cells that elicit a barrage of cytotoxic effectors. Alternatively, antigens from extracellular pathogens are captured by MHCII molecules after digestion in the phagolysosome and presented to CD4+ that elicit a burst of cytokines that activate B cells to produce an antibody response. Abbreviations and notations; bold arrow () indicates steps during the progression of BSI and sepsis; unbolded arrow () indicates activation of pathway; () indicates inhibition of pathway; curved unbolded arrow () indicates production; MΦ, macrophage; PMN, polymorphonuclear neutrophil; LTA, lipotechoic acid; PG, petidoglycan; LPS, lipopolysaccharide; IgG, Immunoglobulin G; IgA, Immunoglobulin A; sIGA, secretory IgA; CR1, Complement Receptor 1; Fe, iron; IroN, siderophore; TIR, TLR/Interleukin-1 receptor; Nod1/2, cytoplasmic PAMP receptors; ROS, reactive oxygen species; TCR, T cell receptor; TAP, transporter associated with antigen processing; ER, endoplasmic reticulum; APC, antigen presenting cell; MHCI/II, major histocompatability complex I/II; Ag, antigen; CD4+, T cell co-receptor distinguishing T helper cells; CD8+ T cell co-receptor distinguishing cytotoxic T cells.