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Seasonal epidemics erupt commonly in nature and are driven by numerous mechanisms. Here, we suggest a new mechanism that could determine the size and timing of seasonal epidemics: rearing environment changes the performance of parasites. This mechanism arises when the environmental conditions in which a parasite is produced impact its performance—independently from the current environment. To illustrate the potential for “rearing effects”, we show how temperature influences infection risk (transmission rate) in a Daphnia-fungus disease system through both parasite rearing temperature and infection temperature. During autumnal epidemics, zooplankton hosts contact (eat) fungal parasites (spores) reared in a gradually cooling environment. To delineate the effect of rearing temperature from temperature at exposure and infection, we used lab experiments to parameterize a mechanistic model of transmission rate. We also evaluated the rearing effect using spores collected from epidemics in cooling lakes. We found that fungal spores were more infectious when reared at warmer temperatures (in the lab and in two of three lakes). Additionally, the exposure (foraging) rate of hosts increased with warmer infection temperatures. Thus, both mechanisms cause transmission rate to drop as temperature decreases over the autumnal epidemic season (from summer to winter). Simulations show how these temperature-driven changes in transmission rate can induce waning of epidemics as lakes cool. Furthermore, via thermally dependent transmission, variation in environmental cooling patterns can alter the size and shape of epidemics. Thus, the thermal environment drives seasonal epidemics through effects on hosts (exposure rate) and the infectivity of parasites (a rearing effect). Presently, the generality of parasite rearing effects remains unknown. Our results suggest that they may provide an important but underappreciated mechanism linking temperature to the seasonality of epidemics.

Introduction In immunocompromised patients, acute respiratory failure (ARF) is associated with high mortality, particularly when invasive mechanical ventilation (IMV) is required. In patients with severe hypoxemia, high-flow nasal oxygen (HFNO) therapy has been used as an alternative to delivery of oxygen via a Venturi mask. Our objective in the present study was to compare HFNO and Venturi mask oxygen in immunocompromised patients with ARF. Methods We conducted a multicenter, parallel-group randomized controlled trial in four intensive care units. Inclusion criteria were hypoxemic ARF and immunosuppression, defined as at least one of the following: solid or hematological malignancy, steroid or other immunosuppressant drug therapy, and HIV infection. Exclusion criteria were hypercapnia, previous IMV, and immediate need for IMV or noninvasive ventilation (NIV). Patients were randomized to 2 h of HFNO or Venturi mask oxygen. Results The primary endpoint was a need for IMV or NIV during the 2-h oxygen therapy period. Secondary endpoints were comfort, dyspnea, and thirst, as assessed hourly using a 0–10 visual analogue scale. We randomized 100 consecutive patients, including 84 with malignancies, to HFNO (n = 52) or Venturi mask oxygen (n = 48). During the 2-h study treatment period, 12 patients required IMV or NIV, and we found no significant difference between the two groups (15 % with HFNO and 8 % with the Venturi mask, P  = 0.36). None of the secondary endpoints differed significantly between the two groups. Conclusions In immunocompromised patients with hypoxemic ARF, a 2-h trial with HFNO improved neither mechanical ventilatory assistance nor patient comfort compared with oxygen delivered via a Venturi mask. However, the study was underpowered because of the low event rate and the one-sided hypothesis. Trial registration ClinicalTrials.gov identifier: NCT02424773 . Registered 20 April 2015.

Purpose Immunoparalysis defined by prolonged monocyte human leukocyte antigen DR depression is associated with adverse outcomes in adult severe sepsis and can be reversed with granulocyte macrophage colony-stimulating factor (GM-CSF). We hypothesized that immunoparalysis defined by whole-blood ex vivo lipopolysaccharide-induced tumor necrosis factor-alpha (TNFα) response <200 pg/mL beyond day 3 of multiple organ dysfunction syndrome (MODS) is similarly associated with nosocomial infection in children and can be reversed with GM-CSF. Methods In study period 1, we performed a multicenter cohort trial of transplant and nontransplant multiple organ dysfunction syndrome (MODS) patients (≥2 organ failure). In study period 2, we performed an open-label randomized trial of GM-CSF therapy for nonneutropenic, nontransplant, severe MODS patients (≥3 organ failure) with TNFα response <160 pg/mL. Results Immunoparalysis was observed in 34% of MODS patients ( n  = 70) and was associated with increased nosocomial infection (relative risk [RR] 3.3, 95% confidence interval [1.8–6.0] p  < 0.05) and mortality (RR 5.8 [2.1–16] p  < 0.05). TNFα response <200 pg/mL throughout 7 days after positive culture was associated with persistent nosocomial infection, whereas recovery above 200 pg/mL was associated with resolution of infection ( p  < 0.05). In study period 2, GM-CSF therapy facilitated rapid recovery of TNFα response to >200 pg/mL by 7 days ( p  < 0.05) and prevented nosocomial infection (no infections in seven patients versus eight infections in seven patients) ( p  < 0.05). Conclusions Similar to in adults, immunoparalysis is a potentially reversible risk factor for development of nosocomial infection in pediatric MODS. Whole-blood ex vivo TNFα response is a promising biomarker for monitoring this condition.

Interferon-induced transmembrane proteins (IFITMs 1, 2 and 3) can restrict viral pathogens, but pro- and anti-viral activities have been reported for coronaviruses. Here, we show that artificial overexpression of IFITMs blocks SARS-CoV-2 infection. However, endogenous IFITM expression supports efficient infection of SARS-CoV-2 in human lung cells. Our results indicate that the SARS-CoV-2 Spike protein interacts with IFITMs and hijacks them for efficient viral infection. IFITM proteins were expressed and further induced by interferons in human lung, gut, heart and brain cells. IFITM-derived peptides and targeting antibodies inhibit SARS-CoV-2 entry and replication in human lung cells, cardiomyocytes and gut organoids. Our results show that IFITM proteins are cofactors for efficient SARS-CoV-2 infection of human cell types representing in vivo targets for viral transmission, dissemination and pathogenesis and are potential targets for therapeutic approaches. IFITM proteins can inhibit several viruses, but effects on SARS-CoV-2 infection are not well understood. Here, the authors show that endogenous IFITMs support SARS-CoV-2 infection in different in vitro models by binding spike and enhancing virus entry.

A sea cage, sometimes referred to as a net pen, is an enclosure designed to prevent farm fish from escaping and to protect them from large predators, while allowing a free flow of water through the cage to carry away waste. Farm fish thus share water with wild fish, which enables transmission of parasites, such as sea lice, from wild to farm and farm to wild fishes. Sea lice epidemics, together with recently documented population-level declines of wild salmon in areas of sea-cage farming, are a reminder that sea-cage aquaculture is fundamentally different from terrestrial animal culture. The difference is that sea cages protect farm fish from the usual pathogen-control mechanisms of nature, such as predators, but not from the pathogens themselves. A sea cage thus becomes an unintended pathogen factory. Basic physical theory explains why sea-cage aquaculture causes sea lice on sympatric wild fish to increase and why increased lice burdens cause wild fish to decline, with extirpation as a real possibility. Theory is important to this issue because slow declines of wild fish can be difficult to detect amid large fluctuations from other causes. The important theoretical concepts are equilibrium, host-density effect, reservoir-host effect, and critical stocking level of farmed fish (stocking level at which lice proliferate on farm fish even if wild fish are not present to infect them). I explored these concepts and their implications without mathematics through examples from salmon farming. I also considered whether the lice-control techniques used by sea-cage farmers (medication and shortened grow-out times) are capable of protecting wild fish. Elementary probability showed that [graphic removed] (where W is the abundance of wild fish, W* is the prefarm abundance, F is the abundance of farm fish, and [graphic removed] is the ratio of lice per farm fish to lice per wild fish). Declines of wild fish can be reduced by short growing cycles for farm fish, medicating farm fish, and keeping farm stocking levels low. Declines can be avoided only by ensuring that wild fish do not share water with farmed fish, either by locating sea cages very far from wild fish or through the use of closed-containment aquaculture systems. These principles are likely to govern any aquaculture system where cage-protected farm hosts and sympatric wild hosts have a common parasite with a direct life cycle.

Aberrant microbiota composition and function have been linked to several pathologies, including type 2 diabetes. In animal models, prebiotics induce favourable changes in the intestinal microbiota, intestinal permeability (IP) and endotoxaemia, which are linked to concurrent improvement in glucose tolerance. This is the first study to investigate the link between IP, glucose tolerance and intestinal bacteria in human type 2 diabetes. In all, twenty-nine men with well-controlled type 2 diabetes were randomised to a prebiotic (galacto-oligosaccharide mixture) or placebo (maltodextrin) supplement (5·5 g/d for 12 weeks). Intestinal microbial community structure, IP, endotoxaemia, inflammatory markers and glucose tolerance were assessed at baseline and post intervention. IP was estimated by the urinary recovery of oral 51Cr-EDTA and glucose tolerance by insulin-modified intravenous glucose tolerance test. Intestinal microbial community analysis was performed by high-throughput next-generation sequencing of 16S rRNA amplicons and quantitative PCR. Prebiotic fibre supplementation had no significant effects on clinical outcomes or bacterial abundances compared with placebo; however, changes in the bacterial family Veillonellaceae correlated inversely with changes in glucose response and IL-6 levels (r −0·90, P=0·042 for both) following prebiotic intake. The absence of significant changes to the microbial community structure at a prebiotic dosage/length of supplementation shown to be effective in healthy individuals is an important finding. We propose that concurrent metformin treatment and the high heterogeneity of human type 2 diabetes may have played a significant role. The current study does not provide evidence for the role of prebiotics in the treatment of type 2 diabetes.

Background: Early host-microbe interaction provides important maturational stimuli for the developing immune system. The role of prenatal microbial contact remains elusive. Objectives: Our aim was to investigate whether microbes in placenta or amniotic fluid affect fetal innate immune gene expression during late pregnancy and whether innate immune gene expression profiles in the placenta and the fetal gut may be modulated by dietary supplementation with specific probiotics. Methods: Altogether 43 pregnant women were randomized to receive (1) Bifidobacterium lactis, (2) B. lactis in combination with Lactobacillus rhamnosus GG (LGG) or (3) placebo for 14 days before elective cesarian section at full term in a double-blind clinical trial. Bacteria in amniotic fluid and placenta were detected by quantitative (q)PCR. The expression of Toll-like receptor (TLR)-related genes in the placenta and meconium samples was assessed by qPCR. Gene expression patterns in meconium were interpreted to reflect immune physiology in the fetal gut. Results: The study was completed by 29 mother-infant pairs. Bacterial DNA was detected in all placenta samples. Microbial DNA in amniotic fluid and placenta was associated with changes in TLR-related gene expression in the fetal intestine. Maternal probiotic supplementation significantly modulated the expression of TLR-related genes both in the placenta and in the fetal gut. Conclusions: Microbial contact in utero is associated with changes in fetal intestinal innate immune gene expression profile. Fetal and placental immune physiology may be modulated by maternal dietary intervention using specific probiotics.

Opportunistic fungal pathogens may cause an array of superficial infections or serious invasive infections, especially in immunocompromised patients. Cryptococcus neoformans is a pathogen causing cryptococcosis in HIV/AIDS patients, but treatment is limited due to the relative lack of potent antifungal agents. Photodynamic inactivation (PDI) uses the combination of non-toxic dyes called photosensitizers and harmless visible light, which produces singlet oxygen and other reactive oxygen species that produce cell inactivation and death. We report the use of five structurally unrelated photosensitizers (methylene blue, Rose Bengal, selenium derivative of a Nile blue dye, a cationic fullerene and a conjugate between poly-L-lysine and chlorin(e6)) combined with appropriate wavelengths of light to inactivate C. neoformans. Mutants lacking capsule and laccase, and culture conditions that favoured melanin production were used to probe the mechanisms of PDI and the effect of virulence factors. The presence of cell wall, laccase and melanin tended to protect against PDI, but the choice of the appropriate photosensitizers and dosimetry was able to overcome this resistance.

Freshwater mussels in the order Unionida are highly adapted to parasitize fish for the primary purpose of dispersal. The parasitic larval stage affixes itself to the gills or fins of the host where it becomes encysted in the tissue, eventually excysting to develop into a free-living adult. Research on the parasitic interactions between unionids and their host fishes has garnered attention recently due to the increase in worldwide preservation efforts surrounding this highly endangered and ecologically significant order. With the exception of heavy infestation events, these mussels cause minor effects to their hosts, typically only observable effect in combination with other stressors. Moreover, the range of effect intensities on the host varies greatly with the species involved in the interaction, an effect that may arise from different evolutionary strategies between long- and short-infesting mussels; a distinction not typically made in conservation practices. Lower growth and reduced osmotic potential in infested hosts are commonly observed and correlated with infestation load. These effects are typically also associated with increases in metabolic rate and behaviour indicative of stress. Host fish seem to compensate for this through a combination of rapid wound healing in the parasitized areas and higher ventilation rates. The findings are heavily biased towards Margaritifera margaritifera, a unique mussel not well suited for cross-species generalizations. Furthermore, the small body of molecular and genetic studies should be expanded as many conclusions are drawn from studies on the ultimate effects of glochidiosis rather than proximate studies on the underlying mechanisms.

Busulfan treatment as a chemotherapeutic agent has been considered an alternative approach in xenograft model because it offers a simple, convenient, effective, and less toxic conditioning regimen. To investigate busulfan effects on the reconstitution of human immune cells and the generation of immune response to foreign antigens, we generated humanized NOD/SCID/IL-2Rγ(null) (NSG) mice conditioned either busulfan or total body irradiation (TBI) with hCD34(+) CB cells. Busulfan resulted in a high survival rate and effective reconstitution of human immune cells including B, T, macrophage, and dendritic cells in humanized NSG mice, compared to that of TBI. Moreover, the humanized NSG mice conditioned busulfan showed effective B cell development and thereby the high production of human antibody against immunized antigen. Humanized mice conditioned by busulfan provide a powerful and versatile tool for studying the entire process of human B-lymphocyte development and for producing specific human antibodies.