Respiratory syncytial virus infection provides protection against severe acute respiratory syndrome coronavirus challenge.

Unlabelled: Respiratory infections are a major health burden worldwide. Respiratory syncytial virus (RSV) is among the leading causes of hospitalization in both young children and older adults. The onset of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic and the public health response had a profound impact on the normal seasonal outbreaks of other respiratory viruses.

Pharmacological ascorbate as a novel therapeutic strategy to enhance cancer immunotherapy.

Pharmacological ascorbate (i.e., intravenous infusions of vitamin C reaching ~ 20 mM in plasma) is under active investigation as an adjuvant to standard of care anti-cancer treatments due to its dual redox roles as an antioxidant in normal tissues and as a prooxidant in malignant tissues.

Pharmacological ascorbate improves the response to platinum-based chemotherapy in advanced stage non-small cell lung cancer.

Purpose: Platinum-based chemotherapy with or without immunotherapy is the mainstay of treatment for advanced stage non-small cell lung cancer (NSCLC) lacking a molecular driver alteration. Pre-clinical studies have reported that pharmacological ascorbate (P-AscH-) enhances NSCLC response to platinum-based therapy. We conducted a phase II clinical trial combining P-AscH- with carboplatin-paclitaxel chemotherapy.

Respiratory Syncytial Virus Provides Protection against a Subsequent Influenza A Virus Infection.

Respiratory infections are a leading cause of morbidity and mortality. The presence of multiple heterologous virus infections is routinely observed in a subset of individuals screened for the presence of respiratory viruses. However, the impact overlapping infections has on disease severity and the host immune response is not well understood.

Intratumoral talimogene laherparepvec injection with concurrent preoperative radiation in patients with locally advanced soft-tissue sarcoma of the trunk and extremities: phase IB/II trial.

Background: Soft-tissue sarcomas (STS) in the extremities and trunk treated with standard-of-care preoperative external beam radiation therapy (EBRT) followed by surgical resection are associated with local and distant relapses. In preclinical studies, oncolytic virotherapy in sarcoma has demonstrated antitumor effects via direct intratumoral oncolysis and cytotoxic T-cell-mediated immune responses. Talimogene laherparepvec (TVEC) is a replication-competent, immune-enhanced, oncolytic herpes simplex virus type 1 engineered for intratumoral injection; it has been approved by the FDA for the treatment of locally advanced and metastatic melanoma.

Protective function and durability of mouse lymph node-resident memory CD8 T cells.

Protective lung tissue-resident memory CD8T cells (Trm) form after influenza A virus (IAV) infection. We show that IAV infection of mice generates CD69CD103and other memory CD8T cell populations in lung-draining mediastinal lymph nodes (mLNs) from circulating naive or memory CD8T cells. Repeated antigen exposure, mimicking seasonal IAV infections, generates quaternary memory (4M) CD8T cells that protect mLN from viral infection better than 1M CD8T cells.

Tissue-Resident Memory T Cells in the Lungs Protect against Acute Respiratory Syncytial Virus Infection.

Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infection in young children. The T cell response plays a critical role in facilitating clearance of an acute RSV infection, and memory T cell responses are vital for protection against secondary RSV exposures. Tissue-resident memory (TRM) T cells have been identified as a subset of memory T cells that reside in nonlymphoid tissues and are critical for providing long-term immunity.

Memory CD8 T cells mediate severe immunopathology following respiratory syncytial virus infection.

Memory CD8 T cells can provide protection from re-infection by respiratory viruses such as influenza and SARS. However, the relative contribution of memory CD8 T cells in providing protection against respiratory syncytial virus (RSV) infection is currently unclear. To address this knowledge gap, we utilized a prime-boost immunization approach to induce robust memory CD8 T cell responses in the absence of RSV-specific CD4 T cells and antibodies.

Revealing the Complexity in CD8 T Cell Responses to Infection in Inbred C57B/6 versus Outbred Swiss Mice.

Recent work has suggested that current mouse models may underrepresent the complexity of human immune responses. While most mouse immunology studies utilize inbred mouse strains, it is unclear if conclusions drawn from inbred mice can be extended to all mouse strains or generalized to humans. We recently described a "surrogate activation marker" approach that could be used to track polyclonal CD8 T cell responses in inbred and outbred mice and noted substantial discord in the magnitude and kinetics of CD8 T cell responses in individual outbred mice following infection.

Polymicrobial sepsis impairs bystander recruitment of effector cells to infected skin despite optimal sensing and alarming function of skin resident memory CD8 T cells.

Sepsis is a systemic infection that enhances host vulnerability to secondary infections normally controlled by T cells. Using CLP sepsis model, we observed that sepsis induces apoptosis of circulating memory CD8 T-cells (TCIRCM) and diminishes their effector functions, leading to impaired CD8 T-cell mediated protection to systemic pathogen re-infection. In the context of localized re-infections, tissue resident memory CD8 T-cells (TRM) provide robust protection in a variety of infectious models.

Host genetics play a critical role in controlling CD8 T cell function and lethal immunopathology during chronic viral infection.

Effective CD8 T cell responses are vital for the control of chronic viral infections. Many factors of the host immune response contribute to the maintenance of effector CD8 T cell responses versus CD8 T cell exhaustion during chronic infection. Specific MHC alleles and the degree of MHC heterogeneity are associated with enhanced CD8 T cell function and viral control during human chronic infection.

The transcription factor Runx3 guards cytotoxic CD8 effector T cells against deviation towards follicular helper T cell lineage.

Activated CD8 T cells differentiate into cytotoxic effector (T) cells that eliminate target cells. How T cell identity is established and maintained is not fully understood. We found that Runx3 deficiency limited clonal expansion and impaired upregulation of cytotoxic molecules in T cells.

Antigen Exposure History Defines CD8 T Cell Dynamics and Protection during Localized Pulmonary Infections.

Unlike systemic infections, little is known about the role of repeated localized infections on (re)shaping pathogen-specific memory CD8 T cell responses. Here, we used primary (1°) and secondary (2°) intranasal influenza virus infections of mice as a model to study intrinsic memory CD8 T cell properties. We show that secondary antigen exposure, relative to a single infection, generates memory CD8 T cell responses of superior magnitude in multiple tissue compartments including blood, spleen, draining lymph nodes, and lung.

Altered Treg and cytokine responses in RSV-infected infants.

Background: Respiratory syncytial virus (RSV) is the leading cause of bronchiolitis and pneumonia in children under 1 y of age in the USA. The host immune response is believed to contribute to RSV-induced disease. We hypothesize that severe RSV infection in infants is mediated by insufficient regulation of the host immune response of regulatory T cells (Tregs) resulting in immunopathology.

Non-typeable Haemophilus influenzae protects human airway epithelial cells from a subsequent respiratory syncytial virus challenge.

Respiratory syncytial virus (RSV) and the common commensal and opportunistic pathogen, non-typeable Haemophilus influenzae (NTHi) both serve as a frequent cause of respiratory infection in children. Although it is well established that some respiratory viruses can increase host susceptibility to secondary bacterial infections, few studies have examined how commensal bacteria could influence a secondary viral response. Here, we examined the impact of NTHi exposure on a subsequent RSV infection of human bronchial epithelial cells (16HBE14o-).

Inflammatory IL-15 is required for optimal memory T cell responses.

Due to their ability to rapidly proliferate and produce effector cytokines, memory CD8+ T cells increase protection following reexposure to a pathogen. However, low inflammatory immunizations do not provide memory CD8+ T cells with a proliferation advantage over naive CD8+ T cells, suggesting that cell-extrinsic factors enhance memory CD8+ T cell proliferation in vivo. Herein, we demonstrate that inflammatory signals are critical for the rapid proliferation of memory CD8+ T cells following infection.

RSV vaccine-enhanced disease is orchestrated by the combined actions of distinct CD4 T cell subsets.

There is no currently licensed vaccine for respiratory syncytial virus (RSV) despite being the leading cause of lower respiratory tract infections in children. Children previously immunized with a formalin-inactivated RSV (FI-RSV) vaccine exhibited enhanced respiratory disease following natural RSV infection. Subsequent studies in animal models have implicated roles for CD4 T cells, eosinophils and non-neutralizing antibodies in mediating enhanced respiratory disease.

The pulmonary localization of virus-specific T lymphocytes is governed by the tissue tropism of infection.

Unlabelled: The migration of pathogen-specific T cells into nonlymphoid tissues, such as the lung, is critical to control peripheral infections. Use of in vivo intravascular labeling of leukocytes has allowed for improved discrimination between cells located in the blood from cells present within peripheral tissues, such as the lung. This is particularly important in the lung, which is comprised of an intricate network of blood vessels that harbors a large proportion of the total blood volume at any given time.

Respiratory syncytial virus increases lung cellular bioenergetics in neonatal C57BL/6 mice.

We have previously reported that lung cellular bioenergetics (cellular respiration and ATP) increased in 4-10 week-old BALB/c mice infected with respiratory syncytial virus (RSV). This study examined the kinetics and changes in cellular bioenergetics in ≤ 2-week-old C57BL/6 mice following RSV infection. Mice (5-14 days old) were inoculated intranasally with RSV and the lungs were examined on days 1-10 post-infection.

Depletion of alveolar macrophages ameliorates virus-induced disease following a pulmonary coronavirus infection.

Coronaviruses cause respiratory disease in humans that can range from mild to severe. However, the pathogenesis of pulmonary coronavirus infections is poorly understood. Mouse hepatitis virus type 1 (MHV-1) is a group 2 coronavirus capable of causing severe morbidity and mortality in highly susceptible C3H/HeJ mice.

Cellular bioenergetics, caspase activity and glutathione in murine lungs infected with influenza A virus.

Inhibition of cellular respiration, oxidation of glutathione and induction of apoptosis have been reported in epithelial cells infected in vitro with influenza A virus (IAV). Here, the same biomarkers were investigated in vivo by assessing the lungs of BALB/c mice infected with IAV. Cellular respiration declined on day 3 and recovered on day 7 post-infection.

Bioenergetics of murine lungs infected with respiratory syncytial virus.

Background: Cellular bioenergetics (cellular respiration and accompanying ATP synthesis) is a highly sensitive biomarker of tissue injury and may be altered following infection. The status of cellular mitochondrial O(2) consumption of the lung in pulmonary RSV infection is unknown.

Methods: In this study, lung fragments from RSV-infected BALB/c mice were evaluated for cellular O(2) consumption, ATP content and caspase activity.

Lung tissue bioenergetics and caspase activity in rodents.

Background: This study aimed to establish a suitable in vitro system for investigating effects of respiratory pathogens and toxins on lung tissue bioenergetics (cellular respiration and ATP content) and caspase activity. Wistar rats and C57Bl/6 mice were anesthetized by sevoflurane inhalation. Lung fragments were then collected and incubated at 37°C in a continuously gassed (with 95% O2:5% CO2) Minimal Essential Medium (MEM) or Krebs-Henseleit buffer.

Protective and pathologic roles of the immune response to mouse hepatitis virus type 1: implications for severe acute respiratory syndrome.

Intranasal mouse hepatitis virus type 1 (MHV-1) infection of mice induces lung pathology similar to that observed in severe acute respiratory syndrome (SARS) patients. However, the severity of MHV-1-induced pulmonary disease varies among mouse strains, and it has been suggested that differences in the host immune response might account for this variation. It has also been suggested that immunopathology may represent an important clinical feature of SARS.