Elevated temperature inhibits SARS-CoV-2 replication in respiratory epithelium independently of IFN-mediated innate immune defenses

The pandemic spread of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the etiological agent of Coronavirus Disease 2019 (COVID-19), represents an ongoing international health crisis. A key symptom of SARS-CoV-2 infection is the onset of fever, with a hyperthermic temperature range of 38 to 41°C. Fever is an evolutionarily conserved host response to microbial infection that can influence the outcome of viral pathogenicity and regulation of host innate and adaptive immune responses. However, it remains to be determined what effect elevated temperature has on SARS-CoV-2 replication. Utilizing a three-dimensional (3D) air–liquid interface (ALI) model that closely mimics the natural tissue physiology of SARS-CoV-2 infection in the respiratory airway, we identify tissue temperature to play an important role in the regulation of SARS-CoV-2 infection. Respiratory tissue incubated at 40°C remained permissive to SARS-CoV-2 entry but refractory to viral transcription, leading to significantly reduced levels of viral RNA replication and apical shedding of infectious virus. We identify tissue temperature to play an important role in the differential regulation of epithelial host responses to SARS-CoV-2 infection that impact upon multiple pathways, including intracellular immune regulation, without disruption to general transcription or epithelium integrity. We present the first evidence that febrile temperatures associated with COVID-19 inhibit SARS-CoV-2 replication in respiratory epithelia. Our data identify an important role for tissue temperature in the epithelial restriction of SARS-CoV-2 independently of canonical interferon (IFN)-mediated antiviral immune defenses.

Pyocyanin pigment from Pseudomonas aeruginosa modulates innate immune defenses in macrophages

Background: Pseudomonas aeruginosa is a well-known opportunistic pathogen. The gram-negative bacillus, commonly associated with hospital-acquired infections, utilizes the host’s impaired immune responses to establish infection. Of its many virulence factors, pyocyanin is essential for P. aeruginosa to establish its full infectivity. Macrophages act as sentinels of the innate immune system, as well as play other roles in homeostasis, tissue remodeling, and bridging between the innate and adaptive immune systems. Aim: This study aimed to investigate the effects of pyocyanin on macrophage innate immune defenses by assessing the function of macrophages treated with pyocyanin and TLR ligands. Phagocytosis of opsonized zymosan, LPS-induced nitric oxide release and cytokine release were used as measures of functional responses. Results: This study found that pyocyanin inhibited phagocytosis-induced ROS release in a dose-dependent manner and reduced nitric oxide release from macrophages induced with P. aeruginosa LPS. In addition, pyocyanin modulated cytokines and chemokines release from macrophages exposed to P. aeruginosa LPS in a dose-dependent manner. Pyocyanin significantly enhanced IL-1β release as well as several chemokines. Therefore, pyocyanin facilitates Pseudomonas aeruginosa to persevere in the immunocompromised host through modulating macrophage’s innate immune defenses. Conclusion: Pyocyanin inhibits macrophage functional defense responses to facilitate Pseudomonas aeruginosa infection.

Sterol scarcity primes p38 immune defenses through a TIR-1/SARM1 phase transition

Intracellular signaling regulators can be concentrated into membrane-free, higher-ordered protein assemblies to initiate protective responses during stress - a process known as phase transition. Here, we show that a phase transition of the C. elegans Toll/interleukin-1 receptor domain protein (TIR-1), a homolog of the mammalian sterile alpha and TIR motif-containing 1 (SARM1), primes host immune defenses when dietary sterols are limited to handle subsequent bacterial infection. TIR-1/SARM1 is an upstream component of the p38 PMK-1 pathway in intestinal cells, an innate immune defense and stress response pathway in metazoans. Under conditions of low cholesterol availability, multimerization and precipitation of TIR-1/SARM1 potentiates the intrinsic NAD+ glycohydrolase activity of this protein complex, increases p38 PMK-1 phosphorylation, and promotes pathogen clearance from the intestine. Dietary cholesterol is required for C. elegans to survive infection with pathogenic bacteria and to support development, fecundity, and lifespan. Thus, activation of the p38 PMK-1 pathway in sterol-deficient animals is an adaptive response that allows a metazoan host to anticipate environmental threats under conditions of essential metabolite scarcity.

Ecoimmunology

Avian immune systems are multifaceted and vary widely among individuals, populations, and species, all of which will affect the dynamics of infectious diseases in the wild. Historically, ecoimmunology sought to uncover the proximate and ultimate drivers of heterogeneity in immune defenses. More recently, the field has begun to interface with disease ecology, asking not only about the causes of immune variation but also about its links to within- and between-host disease processes. This chapter briefly reviews the complexity of avian immune systems, outlines theories of how and why these defenses vary, and provides an overview of both common and novel techniques in ecoimmunology. Subsequent sections highlight two research questions as critical to the synergy between ecoimmunology and disease ecology: (1) How do immune phenotypes predict individual infection outcomes? and (2) How do within-host measures of immunity inform population-level transmission dynamics?

Winter is coming–Temperature affects immune defenses and susceptibility to Batrachochytrium salamandrivorans

Environmental temperature is a key factor driving various biological processes, including immune defenses and host-pathogen interactions. Here, we evaluated the effects of environmental temperature on the pathogenicity of the emerging fungal pathogen, Batrachochytrium salamandrivorans (Bsal), using controlled laboratory experiments, and measured components of host immune defense to identify regulating mechanisms. We found that adult and juvenile Notophthalmus viridescens died faster due to Bsal chytridiomycosis at 14°C than at 6 and 22°C. Pathogen replication rates, total available proteins on the skin, and microbiome composition likely drove these relationships. Temperature-dependent skin microbiome composition in our laboratory experiments matched seasonal trends in wild N. viridescens, adding validity to these results. We also found that hydrophobic peptide production after two months post-exposure to Bsal was reduced in infected animals compared to controls, perhaps due to peptide release earlier in infection or impaired granular gland function in diseased animals. Using our temperature-dependent susceptibility results, we performed a geographic analysis that revealed N. viridescens populations in the northeastern United States and southeastern Canada are at greatest risk for Bsal invasion, which shifted risk north compared to previous assessments. Our results indicate that environmental temperature will play a key role in the epidemiology of Bsal and provide evidence that temperature manipulations may be a viable disease management strategy.

Induced Transient Immune Tolerance in Ticks and Vertebrate Host: A Keystone of Tick-Borne Diseases?

Ticks and tick transmitted infectious agents are increasing global public health threats due to increasing abundance, expanding geographic ranges of vectors and pathogens, and emerging tick-borne infectious agents. Greater understanding of tick, host, and pathogen interactions will contribute to development of novel tick control and disease prevention strategies. Tick-borne pathogens adapt in multiple ways to very different tick and vertebrate host environments and defenses. Ticks effectively pharmacomodulate by its saliva host innate and adaptive immune defenses. In this review, we examine the idea that successful synergy between tick and tick-borne pathogen results in host immune tolerance that facilitates successful tick infection and feeding, creates a favorable site for pathogen introduction, modulates cutaneous and systemic immune defenses to establish infection, and contributes to successful long-term infection. Tick, host, and pathogen elements examined here include interaction of tick innate immunity and microbiome with tick-borne pathogens; tick modulation of host cutaneous defenses prior to pathogen transmission; how tick and pathogen target vertebrate host defenses that lead to different modes of interaction and host infection status (reservoir, incompetent, resistant, clinically ill); tick saliva bioactive molecules as important factors in determining those pathogens for which the tick is a competent vector; and, the need for translational studies to advance this field of study. Gaps in our understanding of these relationships are identified, that if successfully addressed, can advance the development of strategies to successfully disrupt both tick feeding and pathogen transmission.