Examining the Executioners, Influenza Associated Secondary Bacterial Pneumonia

Influenza infections typically present mild to moderate morbidities in immunocompetent host and are often resolved within 14 days of infection onset. Death from influenza infection alone is uncommon; however, antecedent influenza infection often leads to an increased susceptibility to secondary bacterial pneumonia. Bacterial pneumonia following viral infection exhibits mortality rates greater than 10-fold of those of influenza alone. Furthermore, bacterial pneumonia has been identified as the major contributor to mortality during each of the previous four influenza pandemics. Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae, and Streptococcus pyogenes are the most prevalent participants in this pathology. Of note, these lung pathogens are frequently found as commensals of the upper respiratory tract. Herein we describe influenza-induced host-changes that lead to increased susceptibility to bacterial pneumonia, review virulence strategies employed by the most prevalent secondary bacterial pneumonia species, and highlight recent findings of bacterial sensing and responding to the influenza infected environment.

TLR7 Ligation Inhibits TLR8 Responsiveness in IL-27-Primed Human THP-1 Monocytes and Macrophages

Regulation of proinflammatory cytokine expression is critical in the face of single-stranded RNA (ssRNA) virus infections. Many viruses, including coronavirus and influenza virus, wreak havoc on the control of cytokine expression, leading to the formation of detrimental cytokine storms. Understanding the regulation and interplay between inflammatory cytokines is critical to the identification of targets involved in controlling the induction of cytokine expression. In this study, we focused on how the antiviral cytokine interleukin-27 (IL-27) regulates signal transduction downstream of Toll-like receptor 7 (TLR7) and TLR8 ligation, which recognize endosomal single-stranded RNA. Given that IL-27 alters bacterial-sensing TLR expression on myeloid cells and can inhibit replication of single-stranded RNA viruses, we investigated whether IL-27 affects expression and function of TLR7 and TLR8. Analysis of IL-27-treated THP-1 monocytic cells and THP-1-derived macrophages revealed changes in mRNA and protein expression of TLR7 and TLR8. Although treatment with IL-27 enhanced TLR7 expression, only TLR8-mediated cytokine secretion was amplified. Furthermore, we demonstrated that imiquimod, a TLR7 agonist, inhibited cytokine and chemokine production induced by a TLR8 agonist, TL8-506. Delineating the immunomodulatory role of IL-27 on TLR7 and TLR8 responses provides insight into how myeloid cell TLR-mediated responses are regulated during virus infection.

IL-6 effector function of group 2 innate lymphoid cells (ILC2) is NOD2 dependent

Cutaneous group 2 innate lymphoid cells (ILC2) are spatially and epigenetically poised to respond to barrier compromise and associated immunological threats. ILC2, lacking rearranged antigen-specific receptors, are primarily activated by damage-associated cytokines and respond with type 2 cytokine production. To investigate ILC2 potential for direct sensing of skin pathogens and allergens, we performed RNA sequencing of ILC2 derived from in vivo challenged human skin or blood. We detected expression of NOD2 and TLR2 by skin and blood ILC2. Stimulation of ILC2 with TLR2 agonist alone not only induced interleukin-5 (IL-5) and IL-13 expression but also elicited IL-6 expression in combination with Staphylococcus aureus muramyl dipeptide (MDP). Heat-killed skin-resident bacteria provoked an IL-6 profile in ILC2 in vitro that was notably impaired in ILC2 derived from patients with nucleotide-binding oligomerization domain-containing protein 2 (NOD2) mutations. In addition, we show that NOD2 signaling can stimulate autophagy in ILC2, which was also impaired in patients with NOD2 mutations. Here, we have identified a role for ILC2 NOD2 signaling in the differential regulation of ILC2-derived IL-6 and have reported a previously unrecognized pathway of direct ILC2 bacterial sensing.

Immunometabolism of Macrophages in Bacterial Infections

Macrophages are important effectors of tissue homeostasis, inflammation and host defense. They are equipped with an arsenal of pattern recognition receptors (PRRs) necessary to sense microbial- or danger-associated molecular patterns (MAMPs/DAMPs) and elicit rapid energetically costly innate immunity responses to protect the organism. The interaction between cellular metabolism and macrophage innate immunity is however not limited to answering the cell’s energy demands. Mounting evidence now indicate that in response to bacterial sensing, macrophages undergo metabolic adaptations that contribute to the induction of innate immunity signaling and/or macrophage polarization. In particular, intermediates of the glycolysis pathway, the Tricarboxylic Acid (TCA) cycle, mitochondrial respiration, amino acid and lipid metabolism directly interact with and modulate macrophage effectors at the epigenetic, transcriptional and post-translational levels. Interestingly, some intracellular bacterial pathogens usurp macrophage metabolic pathways to attenuate anti-bacterial defenses. In this review, we highlight recent evidence describing such host-bacterial immunometabolic interactions.

AIE Active Polyelectrolyte Based Photosensitizers: The Effects of Structure on Antibiotic-Resistant Bacterial Sensing and Killing, and Pollutant Decomposition

A facile and effective multifunctional platform with high bacteria detection sensitivity, good antibacterial activity, and excellent dye decomposition efficiency holds great promise for wastewater treatment. To explore design rationality and...