scholarly journals Mathematical Modeling of Within-Host, Untreated, Cytomegalovirus Infection Dynamics after Allogeneic Transplantation

Viruses ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2292
Author(s):  
Elizabeth R. Duke ◽  
Florencia A. T. Boshier ◽  
Michael Boeckh ◽  
Joshua T. Schiffer ◽  
E. Fabian Cardozo-Ojeda
Keyword(s):  
Mathematical Modeling ◽  
Immune Response ◽  
Target Cell ◽  
Hematopoietic Cell Transplantation ◽  
Viral Infections ◽  
Immune Cell ◽  
Controlled Trial ◽  
Antiviral Treatment ◽  
Serum Samples ◽  
Cell Compartments

Cytomegalovirus (CMV) causes significant morbidity and mortality in recipients of allogeneic hematopoietic cell transplantation (HCT). Whereas insights gained from mathematical modeling of other chronic viral infections such as HIV, hepatitis C, and herpes simplex virus-2 have aided in optimizing therapy, previous CMV modeling has been hindered by a lack of comprehensive quantitative PCR viral load data from untreated episodes of viremia in HCT recipients. We performed quantitative CMV DNA PCR on stored, frozen serum samples from the placebo group of participants in a historic randomized controlled trial of ganciclovir for the early treatment of CMV infection in bone marrow transplant recipients. We developed four main ordinary differential Equation mathematical models and used model selection theory to choose between 38 competing versions of these models. Models were fit using a population, nonlinear, mixed-effects approach. We found that CMV kinetics from untreated HCT recipients are highly variable. The models that recapitulated the observed patterns most parsimoniously included explicit, dynamic immune cell compartments and did not include dynamic target cell compartments, consistent with the large number of tissue and cell types that CMV infects. In addition, in our best-fitting models, viral clearance was extremely slow, suggesting severe impairment of the immune response after HCT. Parameters from our best model correlated well with participants’ clinical risk factors and outcomes from the trial, further validating our model. Our models suggest that CMV dynamics in HCT recipients are determined by host immune response rather than target cell limitation in the absence of antiviral treatment.

Varying Inoculum Dose to Assess the Roles of the Immune Response and Target Cell Depletion by the Pathogen in Control of Acute Viral Infections

2020 ◽  
Vol 82 (3) ◽  
Author(s):  
James R. Moore ◽  
Hasan Ahmed ◽  
Balaji Manicassamy ◽  
Adolfo Garcia-Sastre ◽  
Andreas Handel ◽  
...  
Keyword(s):  
Immune Response ◽  
Target Cell ◽  
Viral Infections ◽  
Cell Depletion ◽  
Inoculum Dose

JP-8 jet fuel exposure suppresses the immune response to viral infections

2008 ◽  
Vol 24 (4) ◽  
pp. 209-216 ◽  
Author(s):  
DT Harris ◽  
D Sakiestewa ◽  
D Titone ◽  
X He ◽  
J Hyde ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Viral Infection ◽  
Viral Infections ◽  
Immune Cell ◽  
Immunosuppressive Agents ◽  
Interleukin 10 ◽  
Jet Fuel ◽  
Us Air Force ◽  
Influenza Viral Infection

The US Air Force has implemented the widespread use of JP-8 jet fuel in its operations, although a thorough understanding of its potential effects upon exposed personnel is unclear. Previous work has reported that JP-8 exposure is immunosuppressive. Exposure of mice to JP-8 for 1 h/day resulted in immediate secretion of two immunosuppressive agents, namely, interleukin-10 and prostaglandin E2. Thus, it was of interest to determine if jet fuel exposure might alter the immune response to infectious agents. The Hong Kong influenza model was used for these studies. Mice were exposed to 1000 mg/m3 JP-8 (1 h/day) for 7 days before influenza viral infection. Animals were infected intra-nasally with virus and followed in terms of overall survival as well as immune responses. All surviving animals were killed 14 days after viral infection. In the present study, JP-8 exposure increased the severity of the viral infection by suppressing the anti-viral immune responses. That is, exposure of mice to JP-8 for 1 h/day for 7 days before infection resulted in decreased immune cell viability after exposure and infection, a greater than fourfold decrease in immune proliferative responses to mitogens, as well as an overall loss of CD3+, CD4+, and CD8+ T cells from the lymph nodes, but not the spleens, of infected animals. These changes resulted in decreased survival of the exposed and infected mice, with only 33% of animals surviving as compared with 50% of mice infected but not jet fuel–exposed (and 100% of mice exposed only to JP-8). Thus, short-term, low-concentration JP-8 jet fuel exposures have significant suppressive effects on the immune system which can result in increased severity of viral infections.

scholarly journals Botanical Drugs and Supplements Affecting the Immune Response in the Time of COVID-19: Implications for Research and Clinical Practice

2020 ◽  
Author(s):  
Thomas Brendler ◽  
Ahmed Al-Harrasi ◽  
Rudolf Bauer ◽  
Stefan Gafner ◽  
Mary Hardy ◽  
...  
Keyword(s):  
Immune Response ◽  
Viral Infections ◽  
Chemical Constituents ◽  
Curcuma Longa ◽  
Antiviral Treatment ◽  
Well Being ◽  
Unique Challenge ◽  
Health Crisis ◽  
Pelargonium Sidoides ◽  
Medicinal Fungi

In times of health crisis, including the current COVID-19 pandemic, the potential benefit of botanical drugs and supplements emerges as a focus of attention, although controversial efficacy claims are rightly a concern. Phytotherapy has an established role in everyday selfcare and health care, and since botanical preparations contain many chemical constituents rather than single compounds, challenges arise in demonstrating efficacy and safety. However, there is ample traditional, empirical and clinical evidence that botanicals can offer some protection and alleviation of disease symptoms as well as promoting general well-being. Newly emerging viral infections, specifically COVID-19, represent a unique challenge in their novelty and absence of established antiviral treatment or immunization. We discuss here the roles and limitations of phytotherapy in helping to prevent and address viral infections, and specifically regarding their effects on immune response. Botanicals with a documented immunomodulatory, immunostimulatory, and anti-inflammatory effect include adaptogens, Boswellia spp., Curcuma longa, Echinacea spp., Glycyrrhiza spp., medicinal fungi, Pelargonium sidoides, salicylate-yielding herbs, and Sambucus spp. We further provide a clinical perspective on applications and safety of these herbs in prevention, onset, progression, and convalescence from respiratory viral infections.

scholarly journals Modified T cells as therapeutic agents

Hematology ◽  
2021 ◽  
Vol 2021 (1) ◽  
pp. 296-302
Author(s):  
Nathan Singh
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Lymphocytes ◽  
B Cell ◽  
Cell Transplantation ◽  
Immune Reconstitution ◽  
Hematopoietic Cell Transplantation ◽  
Viral Infections ◽  
Therapeutic Agents ◽  
B Cell Malignancies

Abstract Immunotherapy is now a well-established modality in the treatment of cancer. Although several platforms to redirect the immune response exist, the use of genetically modified T cells has garnered particular attention in recent years. This is due, in large part, to their success in the treatment of B-cell malignancies. Adoptively transferred T cells have also demonstrated efficacy in the treatment of systemic viral infections that occur following hematopoietic cell transplantation prior to immune reconstitution. Here we discuss the techniques that enable redirection of T lymphocytes to treat cancer or infection and the current indications for these therapies.

scholarly journals Modulation of Adaptive Immunity and Viral Infections by Ion Channels

2021 ◽  
Vol 12 ◽  
Author(s):  
Karen Bohmwald ◽  
Nicolás M. S. Gálvez ◽  
Catalina A. Andrade ◽  
Valentina P. Mora ◽  
José T. Muñoz ◽  
...  
Keyword(s):  
Immune Response ◽  
Ion Channels ◽  
Immune Cells ◽  
Viral Infections ◽  
Immune Cell ◽  
Ion Homeostasis ◽  
Adaptive Immune Response ◽  
Ionic Channels ◽  
Cellular Functions ◽  
Adaptive Immune

Most cellular functions require of ion homeostasis and ion movement. Among others, ion channels play a crucial role in controlling the homeostasis of anions and cations concentration between the extracellular and intracellular compartments. Calcium (Ca2+) is one of the most relevant ions involved in regulating critical functions of immune cells, allowing the appropriate development of immune cell responses against pathogens and tumor cells. Due to the importance of Ca2+ in inducing the immune response, some viruses have evolved mechanisms to modulate intracellular Ca2+ concentrations and the mobilization of this cation through Ca2+ channels to increase their infectivity and to evade the immune system using different mechanisms. For instance, some viral infections require the influx of Ca2+ through ionic channels as a first step to enter the cell, as well as their replication and budding. Moreover, through the expression of viral proteins on the surface of infected cells, Ca2+ channels function can be altered, enhancing the pathogen evasion of the adaptive immune response. In this article, we review those ion channels and ion transporters that are essential for the function of immune cells. Specifically, cation channels and Ca2+ channels in the context of viral infections and their contribution to the modulation of adaptive immune responses.

scholarly journals The Natural History of BK Polyomavirus and the Host Immune Response After Stem Cell Transplantation

2019 ◽  
Author(s):  
Benjamin L Laskin ◽  
Michelle R Denburg ◽  
Susan L Furth ◽  
Taylor Moatz ◽  
Michelle Altrich ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Cell Transplantation ◽  
Kidney Function ◽  
Hematopoietic Cell Transplantation ◽  
Antiviral Treatment ◽  
Host Immune Response ◽  
Risk Of Death ◽  
Asymptomatic Patients ◽  
Bk Polyomavirus

Abstract Background BK polyomavirus (BKPyV) is associated with symptomatic hemorrhagic cystitis after hematopoietic cell transplantation (HCT). Little is known about the host immune response, effectiveness of antiviral treatment, or impact of asymptomatic replication on long-term kidney function. Methods In children and young adults undergoing allogeneic HCT, we quantified BKPyV viruria and viremia (pre-HCT and at Months 1–4, 8, 12, and 24 post-HCT) and tested associations of peak viremia ≥10 000 or viruria ≥109 copies/mL with estimated kidney function (glomerular filtration rate, eGFR) and overall survival at 2 years posttransplant. We examined the factors associated with viral clearance by Month 4, including BKPyV-specific T cells by enzyme-linked immune absorbent spot at Month 3 and cidofovir use. Results We prospectively enrolled 193 participants (median age 10 years) and found that 18% had viremia ≥10 000 copies/mL and 45% had viruria ≥109 copies/mL in the first 3 months post-HCT. Among the 147 participants without cystitis (asymptomatic), 58 (40%) had any viremia. In the entire cohort and asymptomatic subset, having viremia ≥10 000 copies/mL was associated with a lower creatinine/cystatin C eGFR at 2 years post-HCT. Viremia ≥10 000 copies/mL was associated with a higher risk of death (adjusted hazard ratio, 2.2; 95% confidence interval, 1.1–4.2). Clearing viremia was associated with detectable BKPyV-specific T cells and having viremia <10 000 copies/mL, but not cidofovir exposure. Conclusions Screening for BKPyV viremia after HCT identifies asymptomatic patients at risk for kidney disease and reduced survival. These data suggest potential changes to clinical practice, including prospective monitoring for BKPyV viremia to test virus-specific T cells to prevent or treat BKPyV replication.

Homeostasis of dendritic cells in lymphoid organs is controlled by regulation of their precursors via a feedback loop

Blood ◽  
2009 ◽  
Vol 114 (20) ◽  
pp. 4411-4421 ◽  
Author(s):  
Kristin Hochweller ◽  
Tewfik Miloud ◽  
Jörg Striegler ◽  
Shalin Naik ◽  
Günter J. Hämmerling ◽  
...  
Keyword(s):  
Immune Response ◽  
Dendritic Cells ◽  
Mouse Model ◽  
Feedback Loop ◽  
Immune Cell ◽  
Feedback Regulation ◽  
Cell Types ◽  
Active Process ◽  
Differentiation Potential ◽  
Cell Compartments

Abstract Dendritic cells (DCs) are key coordinators of the immune response, governing the choice between tolerance and immunity. Despite their importance, the mechanisms controlling the size of the DC compartment are largely unknown. Using a mouse model allowing continuous DC depletion, we show that maintenance of DC numbers in spleen is an active process mediated by Flt3-L–dependent regulation of precursor differentiation into DCs, rather than by changes in proliferation of the differentiated DCs. In particular, the frequency and differentiation potential of intrasplenic DC precursors increased in response to reduced DC numbers. Levels of Flt3-L, a cytokine required for DC differentiation, increased in the blood after DC depletion and returned to normal levels once the DC compartment filled up again. Our data suggest a feedback regulation of DC homeostasis whereby reduction of the DC pool size promotes differentiation of their precursors, via increased Flt3-L availability. This mechanism is different to those known for other immune cell types, such as the B- and T-cell compartments, whereby lymphopenia induces proliferation of already differentiated lymphocytes.

scholarly journals Protective antibodies elicited by SARS-CoV-2 spike protein vaccination are boosted in the lung after challenge in nonhuman primates

2021 ◽  
pp. eabi4547
Author(s):  
Joseph R. Francica ◽  
Barbara J. Flynn ◽  
Kathryn E. Foulds ◽  
Amy T. Noe ◽  
Anne P. Werner ◽  
...  
Keyword(s):  
Nonhuman Primates ◽  
Viral Infections ◽  
Immune Cell ◽  
Antibody Responses ◽  
Spike Protein ◽  
High Dose ◽  
Post Challenge ◽  
Serum Samples ◽  
Igg Antibody

Adjuvanted soluble protein vaccines have been used extensively in humans for protection against various viral infections based on their robust induction of antibody responses. Here, soluble prefusion-stabilized spike protein trimers (preS dTM) from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were formulated with the adjuvant AS03 and administered twice to nonhuman primates (NHP). Binding and functional neutralization assays and systems serology revealed that the vaccinated NHP developed AS03-dependent multi-functional humoral responses that targeted distinct domains of the spike protein and bound to a variety of FC receptors mediating immune cell effector functions in vitro. The neutralizing 50% inhibitory concentration (IC50) titers for pseudovirus and live SARS-CoV-2 were higher than titers for a panel of human convalescent serum samples. NHP were challenged intranasally and intratracheally with a high dose (3x106 plaque forming units, PFU) of SARS-CoV-2 (USA-WA1/2020 isolate). Two days post-challenge, vaccinated NHP showed rapid control of viral replication in both the upper and lower airways. Notably, vaccinated NHP also had increased spike protein-specific IgG antibody responses in the lung as early as two days post challenge. Moreover, passive transfer of vaccine-induced IgG to hamsters mediated protection from subsequent SARS-CoV-2 challenge. These data show that antibodies induced by the AS03-adjuvanted preS dTM vaccine were sufficient to mediate protection against SARS-CoV-2 in NHP and that rapid anamnestic antibody responses in the lung may be a key mechanism for protection.

Therapeutic Exploitation of Viral Interference

2020 ◽  
Vol 20 (4) ◽  
pp. 423-432 ◽  
Author(s):  
Imre Kovesdi ◽  
Tibor Bakacs
Keyword(s):  
Broad Spectrum ◽  
Viral Infections ◽  
Viral Vector ◽  
Antiviral Treatment ◽  
Type I ◽  
Virus Infections ◽  
Emerging Viruses ◽  
Viral Interference ◽  
Pathogenic Virus ◽  
Hepatitis C Rna

: Viral interference, originally, referred to a state of temporary immunity, is a state whereby infection with a virus limits replication or production of a second infecting virus. However, replication of a second virus could also be dominant over the first virus. In fact, dominance can alternate between the two viruses. Expression of type I interferon genes is many times upregulated in infected epithelial cells. Since the interferon system can control most, if not all, virus infections in the absence of adaptive immunity, it was proposed that viral induction of a nonspecific localized temporary state of immunity may provide a strategy to control viral infections. Clinical observations also support such a theory, which gave credence to the development of superinfection therapy (SIT). SIT is an innovative therapeutic approach where a non-pathogenic virus is used to infect patients harboring a pathogenic virus. : For the functional cure of persistent viral infections and for the development of broad- spectrum antivirals against emerging viruses a paradigm shift was recently proposed. Instead of the virus, the therapy should be directed at the host. Such a host-directed-therapy (HDT) strategy could be the activation of endogenous innate immune response via toll-like receptors (TLRs). Superinfection therapy is such a host-directed-therapy, which has been validated in patients infected with two completely different viruses, the hepatitis B (DNA), and hepatitis C (RNA) viruses. SIT exerts post-infection interference via the constant presence of an attenuated non-pathogenic avian double- stranded (ds) RNA viral vector which boosts the endogenous innate (IFN) response. SIT could, therefore, be developed into a biological platform for a new “one drug, multiple bugs” broad-spectrum antiviral treatment approach.

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