Immune status in sepsis: the bug, the site of infection and the severity can make the difference

Studying a large number of patients with sepsis, the Hellenic sepsis study group led by Evangello Giamarellos-Bourboulis emphasizes that the nature of the bacterial infection, its origin (community or nosocomial), its site, and its severity exert different pressures on the immune system. Their study illustrates the heterogeneity of patients with sepsis and points out that numerous key parameters of severe infection influence immune status

Is boosting the immune system in sepsis appropriate?

A relative immunosuppression is observed in patients after sepsis, trauma, burns, or any severe insults. It is currently proposed that selected patients will benefit from treatment aimed at boosting their immune systems. However, the host immune response needs to be considered in context with pathogen-type, timing, and mainly tissue specificity. Indeed, the immune status of leukocytes is not universally decreased and their activated status in tissues contributes to organ failure. Accordingly, any new immune-stimulatory therapeutic intervention should take into consideration potentially deleterious effects in some situations

Новые методы лечения при сепсисе: модели на животных «не работают» (обзор)

Like many other pathological infectious processes, sepsis is mainly studied in vivo using mice models. Over the past 30 years, such studies have led to significant achievements in understanding of the sepsis pathophysiology. However, unfortunately, none of them led to any «discoveries» in the treatment of patients. In this review, we question the relevance of the experimental models applied, list some aspects rarely taken into account and discuss ways to resolve the deadlock.The text is a translation of the article: Cavail-lon J. M. New methods of treating sepsis: failure of animal models, Bull. Assoc. Anc. El. Inst. Pastor, 2017, 59, 230, 58—60. Translation from French by «Akademperevod», Moscow, Russia.Сепсис, как и многие патологические инфекционные процессы, в основном изучается in vivo с использованием моделей на мышах. За последние 30 лет подобные исследования привели к значимым достижениям в понимании патофизиопатологии сепсиса. Однако, к сожалению, ни одно из них не привело к каким-либо «открытиям» в терапии пациентов. В настоящем обзоре мы ставим под сомнение актуальность используемых экспериментальных моделей, перечислим некоторые из редко принимаемых во внимание аспектов и обсудим пути выхода из создавшегося тупика. Ключевые слова: модели на животных; лечение сепсисаТекст является переводом статьи Cavaillon J. M. Nouvelles therapies du sepsis: l'echec des modeles animaux, Bull. Assoc. Anc. El. Inst. Pasteur, 2017, 59, 230, 58—60. Перевод с французского выполнен фирмой «Академперевод», Москва, Россия

Bridging animal and clinical research during SARS-CoV-2 pandemic: A new-old challenge

Model animal; COVID-19; Recerca preclínicaModelo animal; COVID-19; Investigación preclínicaAnimal model; COVID-19; Pre-clinical researchMany milestones in medical history rest on animal modeling of human diseases. The SARS-CoV-2 pandemic has evoked a tremendous investigative effort primarily centered on clinical studies. However, several animal SARS-CoV-2/COVID-19 models have been developed and pre-clinical findings aimed at supporting clinical evidence rapidly emerge. In this review, we characterize the existing animal models exposing their relevance and limitations as well as outline their utility in COVID-19 drug and vaccine development. Concurrently, we summarize the status of clinical trial research and discuss the novel tactics utilized in the largest multi-center trials aiming to accelerate generation of reliable results that may subsequently shape COVID-19 clinical treatment practices. We also highlight areas of improvement for animal studies in order to elevate their translational utility. In pandemics, to optimize the use of strained resources in a short time-frame, optimizing and strengthening the synergy between the preclinical and clinical domains is pivotal

In vivo bioluminescence imaging and histopathopathologic analysis reveal distinct roles for resident and recruited immune effector cells in defense against invasive aspergillosis

BACKGROUND: Invasive aspergillosis (IA) is a major cause of infectious morbidity and mortality in immune compromised patients. Studies on the pathogenesis of IA have been limited by the difficulty to monitor disease progression in real-time. For real-time monitoring of the infection, we recently engineered a bioluminescent A. fumigatus strain. RESULTS: In this study, we demonstrate that bioluminescence imaging can track the progression of IA at different anatomic locations in a murine model of disease that recapitulates the natural route of infection. To define the temporal and functional requirements of distinct innate immune cellular subsets in host defense against respiratory A. fumigatus infection, we examined the development and progression of IA using bioluminescence imaging and histopathologic analysis in mice with four different types of pharmacologic or numeric defects in innate immune function that target resident and recruited phagocyte subsets. While bioluminescence imaging can track the progression and location of invasive disease in vivo, signals can be attenuated by severe inflammation and associated tissue hypoxia. However, especially under non-inflammatory conditions, such as cyclophosphamide treatment, an increasing bioluminescence signal reflects the increasing biomass of alive fungal cells. CONCLUSIONS: Imaging studies allowed an in vivo correlation between the onset, peak, and kinetics of hyphal tissue invasion from the lung under conditions of functional or numeric inactivation of phagocytes and sheds light on the germination speed of conidia under the different immunosuppression regimens. Conditions of high inflammation -either mediated by neutrophil influx under corticosteroid treatment or by monocytes recruited during antibody-mediated depletion of neutrophils- were associated with rapid conidial germination and caused an early rise in bioluminescence post-infection. In contrast, 80% alveolar macrophage depletion failed to trigger a bioluminescent signal, consistent with the notion that neutrophil recruitment is essential for early host defense, while alveolar macrophage depletion can be functionally compensated

Interferon-gamma and granulocyte/monocyte colony-stimulating factor production by natural killer cells involves different signaling pathways and the adaptor stimulator of interferon genes (STING)

Natural killer (NK) cells are important for innate immunity in particular through the production of IFN-gamma and GM-CSF. Both cytokines are important in restoration of immune function of tolerized leukocytes under inflammatory events. The expression of TLRs in NK cells has been widely studied by analyzing the mRNA of these receptors, rarely seeking their protein expression. We previously showed that murine spleen NK cells express TLR9 intracellularly and respond to CpG oligodeoxynucleotide (CpG-ODN) by producing IFN-gamma and GM-CSF. However, to get such production the presence of accessory cytokines (such as IL-15 and IL-18) was required, whereas CpG-ODN or accessory cytokines alone did not induce IFN-gamma or GM-CSF. We show here that TLR9 overlaps with the Golgi apparatus in NK cells. Furthermore, CpG-ODN stimulation in the presence of accessory cytokines induces the phosphorylation of c-Jun, STAT3, and IkappaBalpha. IFN-gamma and GM-CSF production requires NF-kappaB and STAT3 activation as well as Erk-dependent mechanisms for IFN-gamma and p38 signaling for GM-CSF. Using knock-out-mice, we show that UNC93b1 and IL-12 (produced by NK cells themselves) are also necessary for IFN-gamma and GM-CSF production. IFN-gamma production was found to be MyD88- and TLR9-dependent, whereas GM-CSF was TLR9-independent but dependent on STING (stimulator of interferon genes), a cytosolic adaptor recently described for DNA sensing. Our study thereby allows us to gain insight into the mechanisms of synergy between accessory cytokines and CpG-ODN in NK cells. It also identifies a new and alternative signaling pathway for CpG-ODN in murine NK cells