The Altered Neonatal CD8 T Cell Immunodominance Hierarchy during Influenza Virus Infection Impacts Peptide Vaccination.

Neonates are more susceptible to influenza virus infection than adults, resulting in increased morbidity and mortality and delayed clearance of the virus. Generating effective CD8 T cell responses may be important for improving vaccination outcomes in vulnerable populations, but neonatal T cells frequently respond differently than adult cells. We sought to understand CD8 T cell specificity and immunodominance during neonatal influenza infection and how any differences from the adult hierarchy might impact peptide vaccine effectiveness.

Unfolded Von Willebrand Factor Binds Protein S and Reduces Anticoagulant Activity.

Protein S (PS), the critical plasma cofactor for the anticoagulants tissue factor (TF) pathway inhibitor (TFPI) and activated protein C (APC), circulates in two functionally distinct pools: free (anticoagulant) or bound to complement component 4b-binding protein (C4BP) (anti-inflammatory). Acquired free PS deficiency is detected in several viral infections, but its cause is unclear. Here, we identified a shear-dependent interaction between PS and von Willebrand Factor (VWF) by mass spectrometry.

Long-term high-dose immunoglobulin successfully treats Long COVID patients with pulmonary, neurologic, and cardiologic symptoms.

Introduction: Long COVID is the overarching name for a wide variety of disorders that may follow the diagnosis of acute SARS-COVID-19 infection and persist for weeks to many months. Nearly every organ system may be affected.

Methods: We report nine patients suffering with Long COVID for 101 to 547 days.

Total Plasma Protein S Is a Prothrombotic Marker in People Living With HIV.

Background: HIV-1 infection is associated with multiple procoagulant changes and increased thrombotic risk. Possible mechanisms for this risk include heigthened expression of procoagulant tissue factor (TF) on circulating monocytes, extracellular vesicles, and viral particles and/or acquired deficiency of protein S (PS), a critical cofactor for the anticoagulant protein C (PC). PS deficiency occurs in up to 76% of people living with HIV-1 (PLWH).

Bias of the Immune Response to Does Not Alter the Ability of Neonatal Mice to Clear the Infection.

Newborn mice are unable to clear (PC) infection with the same efficiency as adults due, in part, to their inability to develop a robust immune response to infection until three weeks of age. It is known that infants tend develop a Th2 skewed response to antigen so we sought to determine whether a biased cytokine response altered the clearance of PC infection in neonatal mice. infection in neonatal mice resulted in increased IL-4 expression by CD4 T cells and myeloid cells, augmented IL-13 secretion within the airways and increased arginase activity in the airways, indicative of Th2-type responses.

Myeloid arginase-1 controls excessive inflammation and modulates T cell responses in Pseudomonas aeruginosa pneumonia.

Regulatory properties of macrophages associated with alternative activation serve to limit the exaggerated inflammatory response during pneumonia caused by Pseudomonas aeruginosa infection. Arginase-1 is an important effector of these macrophages believed to play an essential role in decreasing injury and promoting repair. We investigated the role of arginase-1 in the control of inflammatory immune responses to P.

Platelets Endocytose Viral Particles and Are Activated via TLR (Toll-Like Receptor) Signaling.

Objective: Thrombocytopenia is associated with many viral infections suggesting virions interact with and affect platelets. Consistently, viral particles are seen inside platelets, and platelet activation markers are detected in viremic patients. In this article, we sought mechanistic insights into these virion/platelet interactions by examining how platelets endocytose, traffic, and are activated by a model virion.

Latent tuberculosis infection is associated with increased unstimulated levels of interferon-gamma in Lima, Peru.

Background: We previously reported increased unstimulated blood levels of interferon-gamma in persons with latent tuberculosis infection (LTBI) in the United States, suggesting enhanced immune activation in LTBI. To investigate this further in a TB-endemic setting, we assessed interferon-gamma levels in persons with and without LTBI in Peru.

Methods: We analyzed data from patients with and without a recent type 1 (spontaneous) acute myocardial infarction (AMI) who were enrolled from two public hospital networks in Lima, Peru, and underwent LTBI testing using the QuantiFERON® TB Gold In-tube (QFT) assay.

The trophic life cycle stage of Pneumocystis species induces protective adaptive responses without inflammation-mediated progression to pneumonia.

Pneumocystis species are fungal pathogens that cause pneumonia in immunocompromised hosts. Lung damage during Pneumocystis pneumonia is predominately due to the inflammatory immune response. Pneumocystis species have a biphasic life cycle.

The Relationship Between Latent Tuberculosis Infection and Acute Myocardial Infarction.

Background: Tuberculosis has been associated with an increased risk of cardiovascular disease (CVD), including acute myocardial infarction (AMI). We investigated whether latent tuberculosis infection (LTBI) is associated with AMI.

Methods: We conducted a case-control study in 2 large national public hospital networks in Lima, Peru, between July 2015 and March 2017.

The Trophic Life Cycle Stage of the Opportunistic Fungal Pathogen Pneumocystis murina Hinders the Ability of Dendritic Cells To Stimulate CD4 T Cell Responses.

The life cycle of the opportunistic fungal pathogen consists of a trophic stage and an ascus-like cystic stage. Infection with the cyst stage induces proinflammatory immune responses, while trophic forms suppress the cytokine response to multiple pathogen-associated molecular patterns (PAMPs), including β-glucan. A targeted gene expression assay was used to evaluate the dendritic cell response following stimulation with trophic forms alone, with a normal mixture of trophic forms and cysts, or with β-glucan.

Overcoming Hurdles to Development of a Vaccine against Pneumocystis jirovecii.

Development of pneumonia (PCP) is a common problem among immunosuppressed individuals. There are windows of opportunity in which vaccination would be beneficial, but to date, no vaccines have made it to clinical trials. Significant hurdles to vaccine development include host range specificity, making it difficult to translate from animal models to humans.

Pneumocystis infection alters the activation state of pulmonary macrophages.

Recent studies show a substantial incidence of Pneumocystis jirovecii colonization and infection in patients with chronic inflammatory lung conditions. However, little is known about the impact of Pneumocystis upon the regulation of pulmonary immunity. We demonstrate here that Pneumocystis polarizes macrophages towards an alternatively activated macrophage-like phenotype.

The life cycle stages of Pneumocystis murina have opposing effects on the immune response to this opportunistic, fungal pathogen.

The cyst cell wall β-glucans of Pneumocystis have been shown to stimulate immune responses in lung epithelial cells, dendritic cells, and alveolar macrophages. Little is known about how the trophic life forms, which do not have a fungal cell wall, interact with these innate immune cells. Here, we report differences in the responses of both neonatal and adult mice to the trophic and cystic life cycle stages of Pneumocystis murina The adult and neonatal immune responses to infection with Pneumocystis murina trophic forms were less robust than the response to infection with a physiologically normal mixture of cysts and trophic forms.

Tuberculosis and Cardiovascular Disease: Linking the Epidemics.

The burden of tuberculosis and cardiovascular disease (CVD) is enormous worldwide. CVD rates are rapidly increasing in low- and middle-income countries. Public health programs have been challenged with the overlapping tuberculosis and CVD epidemics.

Regulatory T Cells Are Critical for Clearing Influenza A Virus in Neonatal Mice.

We previously reported that neonatal mice infected with influenza A virus (IAV) develop interstitial pneumonia characterized by reduced lung cytokine and chemokine responses. The failure of T cells to infiltrate the airways of neonates correlated with delayed clearance of sublethal IAV infections compared to adults. We hypothesized that negative regulators in the neonatal lungs such as cytokines or T regulatory (Treg) cells are responsible for these differences.

B Lymphocytes Are Required during the Early Priming of CD4+ T Cells for Clearance of Pneumocystis Infection in Mice.

B cells play a critical role in the clearance of Pneumocystis. In addition to production of Pneumocystis-specific Abs, B cells are required during the priming phase for CD4(+) T cells to expand normally and generate memory. Clearance of Pneumocystis was found to be dependent on Ag specific B cells and on the ability of B cells to secrete Pneumocystis-specific Ab, as mice with B cells defective in these functions or with a restricted BCR were unable to control Pneumocystis infection.

B cell production of tumor necrosis factor in response to Pneumocystis murina infection in mice.

Pneumocystis species are opportunistic fungal pathogens that induce tumor necrosis factor (TNF) production by alveolar macrophages. Here we report that B cells from the draining lymph nodes as well as lung CD4(+) T cells are important producers of TNF upon Pneumocystis murina infection. To determine the importance of B cell-derived TNF in the primary response to P.

Linezolid decreases susceptibility to secondary bacterial pneumonia postinfluenza infection in mice through its effects on IFN-γ.

Influenza infection predisposes patients to secondary bacterial pneumonia that contributes significantly to morbidity and mortality. Although this association is well documented, the mechanisms that govern this synergism are poorly understood. A window of hyporesponsiveness following influenza infection has been associated with a substantial increase in local and systemic IFN-γ concentrations.

Alveolar macrophages in neonatal mice are inherently unresponsive to Pneumocystis murina infection.

Pneumocystis pneumonia was first diagnosed in malnourished children and has more recently been found in children with upper respiratory symptoms. We previously reported that there is a significant delay in the immune response in newborn mice infected with Pneumocystis compared to adults (Garvy BA, Harmsen AG, Infect. Immun.

Role of phosphoinositide 3-kinase-Akt signaling pathway in the age-related cytokine dysregulation in splenic macrophages stimulated via TLR-2 or TLR-4 receptors.

Age-associated defects in both B-lymphocytes and macrophages in elderly result in a reduction in the efficacy of vaccines to many Gram positive bacteria like Streptococcus pneumoniae. Splenic macrophages from aged mice have been shown to have a defect in production of pro-inflammatory cytokines (IL-6, IL-12, IL-1β, TNF-α) but exhibit increased production of IL-10 upon TLR-4 ligation. Here we showed that aged macrophages demonstrate similar cytokine dysregulation phenotype upon stimulation with TLR-2 ligands, or killed S.

The migration of T cells in response to influenza virus is altered in neonatal mice.

Influenza virus is a significant cause of mortality and morbidity in children; however, little is known about the T cell response in infant lungs. Neonatal mice are highly vulnerable to influenza and only control very low doses of virus. We compared the T cell response to influenza virus infection between mice infected as adults or at 2 d old and observed defective migration into the lungs of the neonatal mice.

Azithromycin alters macrophage phenotype and pulmonary compartmentalization during lung infection with Pseudomonas.

Infection with mucoid strains of Pseudomonas aeruginosa in chronic inflammatory diseases of the airway is difficult to eradicate and can cause excessive inflammation. The roles of alternatively activated and regulatory subsets of macrophages in this pathophysiological process are not well characterized. We previously demonstrated that azithromycin induces an alternatively activated macrophage-like phenotype in vitro.

Yersinia pestis YadC: a novel vaccine candidate against plague.

Current subunit vaccines provide partial protection against pneumonic plague if the infecting Y. pestis strain is encapsulated (F1+). Here we describe YadC, a novel Y.

Blunted humoral response to influenza vaccination in patients exposed to zidovudine plus trimethoprim-sulfamethoxazole.

Study Objectives: To determine as proof of principle the effect of combination exposure to zidovudine plus trimethoprim-sulfamethoxazole (TMP-SMX) on humoral immune responses to influenza vaccination in patients with human immunodeficiency virus (HIV).

Design: Prospective, open-label trial.

Setting: University-affiliated infectious diseases outpatient clinic.