Pulmonary-Resident Memory Lymphocytes: Pivotal Orchestrators of Local Immunity Against Respiratory Infections

There is increasing evidence that lung-resident memory T and B cells play a critical role in protecting against respiratory reinfection. With a unique transcriptional and phenotypic profile, resident memory lymphocytes are maintained in a quiescent state, constantly surveying the lung for microbial intruders. Upon reactivation with cognate antigen, these cells provide rapid effector function to enhance immunity and prevent infection. Immunization strategies designed to induce their formation, alongside novel techniques enabling their detection, have the potential to accelerate and transform vaccine development. Despite most data originating from murine studies, this review will discuss recent insights into the generation, maintenance and characterisation of pulmonary resident memory lymphocytes in the context of respiratory infection and vaccination using recent findings from human and non-human primate studies.

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The lung–gut axis during viral respiratory infections: the impact of gut dysbiosis on secondary disease outcomes

Mucosal Immunology ◽

10.1038/s41385-020-00361-8 ◽

2021 ◽

Author(s):

Valentin Sencio ◽

Marina Gomes Machado ◽

François Trottein

Keyword(s):

Gut Microbiota ◽

Bacterial Infections ◽

Respiratory Infections ◽

Critical Role ◽

Good Health ◽

Disease Outcomes ◽

And Function ◽

Viral Respiratory Infections ◽

The Impact ◽

Viral Respiratory

AbstractBacteria that colonize the human gastrointestinal tract are essential for good health. The gut microbiota has a critical role in pulmonary immunity and host’s defense against viral respiratory infections. The gut microbiota’s composition and function can be profoundly affected in many disease settings, including acute infections, and these changes can aggravate the severity of the disease. Here, we discuss mechanisms by which the gut microbiota arms the lung to control viral respiratory infections. We summarize the impact of viral respiratory infections on the gut microbiota and discuss the potential mechanisms leading to alterations of gut microbiota’s composition and functions. We also discuss the effects of gut microbial imbalance on disease outcomes, including gastrointestinal disorders and secondary bacterial infections. Lastly, we discuss the potential role of the lung–gut axis in coronavirus disease 2019.

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Non-human primate models of human respiratory infections

Molecular Immunology ◽

10.1016/j.molimm.2021.04.010 ◽

2021 ◽

Vol 135 ◽

pp. 147-164

Author(s):

Julien Lemaitre ◽

Thibaut Naninck ◽

Benoît Delache ◽

Justina Creppy ◽

Philippe Huber ◽

...

Keyword(s):

Respiratory Infections ◽

Human Primate

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Emerging Role of Phospholipase-Derived Cleavage Products in Regulating Eosinophil Activity: Focus on Lysophospholipids, Polyunsaturated Fatty Acids and Eicosanoids

International Journal of Molecular Sciences ◽

10.3390/ijms22094356 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4356

Author(s):

Eva Knuplez ◽

Eva Maria Sturm ◽

Gunther Marsche

Keyword(s):

Fatty Acids ◽

Polyunsaturated Fatty Acids ◽

Critical Role ◽

Allergic Inflammation ◽

Lipid Mediators ◽

Comprehensive Overview ◽

Local Immunity ◽

Effector Cells ◽

Inflammatory Phenotype

Eosinophils are important effector cells involved in allergic inflammation. When stimulated, eosinophils release a variety of mediators initiating, propagating, and maintaining local inflammation. Both, the activity and concentration of secreted and cytosolic phospholipases (PLAs) are increased in allergic inflammation, promoting the cleavage of phospholipids and thus the production of reactive lipid mediators. Eosinophils express high levels of secreted phospholipase A2 compared to other leukocytes, indicating their direct involvement in the production of lipid mediators during allergic inflammation. On the other side, eosinophils have also been recognized as crucial mediators with regulatory and homeostatic roles in local immunity and repair. Thus, targeting the complex network of lipid mediators offer a unique opportunity to target the over-activation and ‘pro-inflammatory’ phenotype of eosinophils without compromising the survival and functions of tissue-resident and homeostatic eosinophils. Here we provide a comprehensive overview of the critical role of phospholipase-derived lipid mediators in modulating eosinophil activity in health and disease. We focus on lysophospholipids, polyunsaturated fatty acids, and eicosanoids with exciting new perspectives for future drug development.

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Plasmodium knowlesi: a relevant, versatile experimental malaria model

Parasitology ◽

10.1017/s0031182016002286 ◽

2016 ◽

Vol 145 (1) ◽

pp. 56-70 ◽

Cited By ~ 8

Author(s):

ERICA M. PASINI ◽

ANNE-MARIE ZEEMAN ◽

ANNEMARIE VOORBERG-VAN DER WEL ◽

CLEMENS H. M. KOCKEN

Keyword(s):

Parasite Species ◽

Vaccine Development ◽

Plasmodium Knowlesi ◽

Host Interactions ◽

Model Studies ◽

Human Red Blood Cells ◽

Malaria Model ◽

Human Primate

SUMMARYThe primate malariaPlasmodium knowlesihas a long-standing history as an experimental malaria model. Studies using this model parasite in combination with its various natural and experimental non-human primate hosts have led to important advances in vaccine development and in our understanding of malaria invasion, immunology and parasite–host interactions. The adaptation to long-termin vitrocontinuous blood stage culture in rhesus monkey,Macaca fascicularisand human red blood cells, as well as the development of various transfection methodologies has resulted in a highly versatile experimental malaria model, further increasing the potential of what was already a very powerful model. The growing evidence thatP. knowlesiis an important human zoonosis in South-East Asia has added relevance to former and future studies of this parasite species.

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The malaria circumsporozoite protein has two functional domains, each with distinct roles as sporozoites journey from mosquito to mammalian host

Journal of Experimental Medicine ◽

10.1084/jem.20101488 ◽

2011 ◽

Vol 208 (2) ◽

pp. 341-356 ◽

Cited By ~ 154

Author(s):

Alida Coppi ◽

Ramya Natarajan ◽

Gabriele Pradel ◽

Brandy L. Bennett ◽

Eric R. James ◽

...

Keyword(s):

Vaccine Development ◽

Critical Role ◽

Domain Architecture ◽

Surface Protein ◽

Circumsporozoite Protein ◽

Mammalian Host ◽

Multifunctional Protein ◽

Mosquito Midgut ◽

Cell Adhesive ◽

Mammalian Liver

Plasmodium sporozoites make a remarkable journey from the mosquito midgut to the mammalian liver. The sporozoite’s major surface protein, circumsporozoite protein (CSP), is a multifunctional protein required for sporozoite development and likely mediates several steps of this journey. In this study, we show that CSP has two conformational states, an adhesive conformation in which the C-terminal cell-adhesive domain is exposed and a nonadhesive conformation in which the N terminus masks this domain. We demonstrate that the cell-adhesive domain functions in sporozoite development and hepatocyte invasion. Between these two events, the sporozoite must travel from the mosquito midgut to the mammalian liver, and N-terminal masking of the cell-adhesive domain maintains the sporozoite in a migratory state. In the mammalian host, proteolytic cleavage of CSP regulates the switch to an adhesive conformation, and the highly conserved region I plays a critical role in this process. If the CSP domain architecture is altered such that the cell-adhesive domain is constitutively exposed, the majority of sporozoites do not reach their target organs, and in the mammalian host, they initiate a blood stage infection directly from the inoculation site. These data provide structure–function information relevant to malaria vaccine development.

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The essential role of sodium bioenergetics and ATP homeostasis in the developmental transitions of a cyanobacterium

10.1101/2020.12.11.421602 ◽

2020 ◽

Author(s):

Sofia Doello ◽

Markus Burkhardt ◽

Karl Forchhammer

Keyword(s):

Energy Homeostasis ◽

Nitrogen Starvation ◽

Critical Role ◽

Quiescent State ◽

Bacterial Survival ◽

Bacterial Populations ◽

Photoautotrophic Growth ◽

Available Energy ◽

Atp Levels

The ability to resume growth after a dormant period is an important strategy for the survival and spreading of bacterial populations. Energy homeostasis is critical in the transition into and out of a quiescent state. Synechocystis sp. PCC 6803, a non-diazotrophic cyanobacterium, enters metabolic dormancy as a response to nitrogen starvation. We used Synechocystis as a model to investigate the regulation of ATP homeostasis during dormancy and unraveled a critical role for sodium bioenergetics in dormant cells. During nitrogen starvation, cells reduce their ATP levels and engage sodium bioenergetics to maintain the minimum ATP content required for viability. When nitrogen becomes available, energy requirements rise, and cells immediately increase ATP levels employing sodium bioenergetics and glycogen catabolism. These processes allow them to restore the photosynthetic machinery and resume photoautotrophic growth. Our work reveals a precise regulation of the energy metabolism essential for bacterial survival during periods of nutrient deprivation.

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Role of Pulmonary Surfactant in Gas Exchange Mechanism and Providing Protection against Progression of any Respiratory Viral Disease like SARS-CoV-2 and Need to focus it as First Point of Medication for all Respiratory Diseases

10.21203/rs.3.rs-692200/v2 ◽

2021 ◽

Author(s):

Makarand Phadke

Keyword(s):

Gas Exchange ◽

Pulmonary Surfactant ◽

Vaccine Development ◽

Critical Role ◽

Physical Property ◽

Lower Surface ◽

Viral Disease ◽

Type I ◽

Mucosal Layer ◽

Unique Physical Property

Abstract During inhalation oxygen molecules are drawn towards type I cells. The partial pressure difference and solubility factor act as a Drive for this movement of oxygen molecules.It is well known that the pulmonary surfactant plays an important role in gas exchange. The surfactant is thin mono-layer. The top surface of surfactant with SP-B and C proteins faces alveolar air and is hydrophobic in nature and acts as a surface tension reducer, whereas lower surface with SP-A and D proteins, is hydrophilic and is adsorbed on mucosal layer. This lower surface of surfactant acts as an anti invader, pathogen barrier. However there is a small missing link in explaining its exact mechanism or role in justifying these properties during normal conditions and during ‘viral ligand’ attack.Similarly a unique physical property of SP- C component is listed in research papers; however its application is not researched anywhere. SP-C has a dielectric constant of 2 to 3 and plays a very critical role in drastically reducing progression of any respiratory viral disease including SARS-CoV-2. This hypothesis targets to explain both micro mechanisms with the help of basic laws of physics, and fluid mechanics. The figures/sketches, drawn also depict the physics involved and not much of a physiology or genetic codes etc. Two examples, in the industry, are briefly listed in the last paragraphs to draw some parallel with above mechanisms.Vaccination is a proven method for containment of a particular respiratory viral disease, if not its cure. But if focus is also given on health of pulmonary surfactant with respect to pathogenesis of any respiratory viral disease, and development of a broad spectrum medication on it; probable loss of lot many lives can be avoided and vaccine development and vaccination management related issues can be less panicky.

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Respiratory infections caused by Haemophilus influenzae β-lactamase positive carrying blaTEM gene

European Journal of Public Health ◽

10.1093/eurpub/ckaa040.057 ◽

2020 ◽

Vol 30 (Supplement_2) ◽

Author(s):

J Valério ◽

H Ferreira ◽

C Chaves ◽

F Rodrigues ◽

N Osório

Keyword(s):

Antibiotic Therapy ◽

Respiratory Infections ◽

Clinical Pathology ◽

Resistance Mechanisms ◽

Important Data ◽

Ampicillin Resistance ◽

Phenotypic Profile ◽

Antimicrobial Susceptibility Profile ◽

Activity Screening ◽

Etiological Agents

Abstract Introduction One of the main etiological agents of respiratory infections is H. Influenzae. The group of antibiotics most used to the treatment of H. influenzae infections is β-lactams. The most common β-lactam resistance is to ampicillin, characterized by the production of TEM (95%) and ROB (5%) β-lactamases, designated enzymatic resistance. Objectives Characterize the susceptibility profile of H. influenzae to β-lactam antibiotics, to evaluate the enzymatic resistance by the β-lactamase production and to correlate the phenotypic profile with the presence of the blaTEM. Methodology Total of 152 isolates of H. influenzae from respiratory infections were evaluated: 88 from expectorations, 56 from bronchial aspirates and 8 from bronchoalveolar lavage, collected in Clinical Pathology Service of Centro Hospitalar e Universitário de Coimbra. The results of the antimicrobial susceptibility profile and the β-lactamase screening were also provided. In order to investigate the blaTEM, DNA was extracted from the isolates and the detection was performed using the PCR technique. Results The prevalence of the blaTEM in the isolates was 31.6%, of these 33.3% showed resistance to ampicillin and 57.9% were positive in β-lactamase activity screening and blaTEM carriers. There was a statistically significance between the presence of the gene with ampicillin resistance and β-lactamase activity screening. Conclusion β-lactamase TEM production was the main mechanism of enzymatic resistance which demonstrates the high spread of the blaTEM among isolates of H. influenzae. The results found suggest that the negative strains for this β-lactamase but that presented β-lactamases with activity and resistance to β-lactams should have other β-lactamases as ROB or others. However strains with β-lactamase negative should have other mechanisms promoting the resistance as PBP3. This study provides important data on the antibiotic therapy, to minimize the expression of resistance mechanisms and problems associated with treatment.

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Dendritic Cells and Cancer: From Biology to Therapeutic Intervention

Cancers ◽

10.3390/cancers11040521 ◽

2019 ◽

Vol 11 (4) ◽

pp. 521 ◽

Cited By ~ 26

Author(s):

Wylie ◽

Macri ◽

Mintern ◽

Waithman

Keyword(s):

Dendritic Cells ◽

Tumor Immunity ◽

Critical Role ◽

Cancer Therapies ◽

Local Immunity ◽

Dc Function ◽

T Cell Infiltration ◽

Anti Cancer ◽

Heterogenous Population ◽

Antigen Presenting

Inducing effective anti-tumor immunity has become a major therapeutic strategy against cancer. Dendritic cells (DC) are a heterogenous population of antigen presenting cells that infiltrate tumors. While DC play a critical role in the priming and maintenance of local immunity, their functions are often diminished, or suppressed, by factors encountered in the tumor microenvironment. Furthermore, DC populations with immunosuppressive activities are also recruited to tumors, limiting T cell infiltration and promoting tumor growth. Anti-cancer therapies can impact the function of tumor-associated DC and/or alter their phenotype. Therefore, the design of effective anti-cancer therapies for clinical translation should consider how best to boost tumor-associated DC function to drive anti-tumor immunity. In this review, we discuss the different subsets of tumor-infiltrating DC and their role in anti-tumor immunity. Moreover, we describe strategies to enhance DC function within tumors and harness these cells for effective tumor immunotherapy.

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2634. Human Metapneumovirus in a Children’s Hospital: It Should Get More Attention

Open Forum Infectious Diseases ◽

10.1093/ofid/ofz360.2312 ◽

2019 ◽

Vol 6 (Supplement_2) ◽

pp. S920-S920

Author(s):

Nellie Said ◽

Wendi Gornick ◽

Beth Huff ◽

Jasjit Singh

Keyword(s):

Disease Surveillance ◽

Vaccine Development ◽

Respiratory Infections ◽

Human Metapneumovirus ◽

Time Period ◽

Potential Vaccine ◽

Syncytial Virus ◽

Viral Respiratory Infections ◽

Hospital Acquired ◽

Viral Respiratory

Abstract Background Viral respiratory infections are a major cause of hospitalization and intensive care unit (ICU) admission to children’s hospitals. Rates of respiratory syncytial virus (RSV) and influenza are closely tracked due to their known morbidity. We had previously observed over one season that human metapneumovirus (hMPV)-infected children have high rates of hospitalizations and ICU admissions, particularly those with chronic lung disease (CLD). We expanded our data to include an additional 5 seasons to compare rates of hospitalizations and hospital-acquired infections (HAIs) due to hMPV, RSV and influenza. Methods During the 2014–2019 winter viral seasons, hMPV, RSV and influenza infections were tracked through both PCR testing (Biofire Respiratory Panel) and DFA testing (D3 Ultra DFA Respiratory Virus Screening & ID Kit; Diagnostic Hybrids). For hMPV admissions, rates of hospitalizations, ICU admissions, HAIs and mortalities were assessed and compared with RSV and influenza admissions. Retrospective data were used to study patients infected with hMPV. Results During the winter seasons of 2014–2019, the rates of hospitalization due to hMPV were significantly higher than both RSV and influenza (Figure 1). ICU admissions and HAIs for hMPV were similar to RSV and influenza (Figures 2 and 3). There were 9 deaths over this time period; 5 due to RSV, 3 due to influenza and 1 due to hMPV. The proportion of deaths due to hMPV compared with RSV and influenza was similar (P = 0.54, 0.89, respectively). Of the 315 total admissions with hMPV, 43 (13.7%) had CLD and 13 (4.1%) were tracheostomy dependent. Among 67 hMPV ICU admissions from 2014–2019, 56 (84%) had an underlying medical diagnosis, 25 (37%) had CLD, 13 (19%) had tracheostomies, and 17 (25%) required mechanical ventilation. The average age of hMPV infected children in our ICU is 4 years 1 month. Conclusion Our large descriptive study of hMPV-infected children over 6 seasons showed higher rates of hospitalization compared with RSV and influenza, similar ICU and HAI rates, and similar rates of mortality. ICU admitted children often had associated co-morbidities, including CLD. Further studies for focused disease surveillance and potential vaccine development for high-risk children are needed. Disclosures All authors: No reported disclosures.

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