Mathematical models of immune effector responses to viral infections: Virus control versus the development of pathology

2005 ◽  
Vol 184 (1) ◽  
pp. 301-319 ◽  
Author(s):  
Dominik Wodarz
2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Iwona Wojcik ◽  
David E. Schmidt ◽  
Lisa A. de Neef ◽  
Minke A. E. Rab ◽  
Bob Meek ◽  
...  

AbstractAs a lymphoid organ, the spleen hosts a wide range of immune cell populations, which not only remove blood-borne antigens, but also generate and regulate antigen-specific immune responses. In particular, the splenic microenvironment has been demonstrated to play a prominent role in adaptive immune responses to enveloped viral infections and alloantigens. During both types of immunizations, antigen-specific immunoglobulins G (IgGs) have been characterized by the reduced amount of fucose present on N-linked glycans of the fragment crystallizable (Fc) region. These glycans are essential for mediating the induction of immune effector functions. Therefore, we hypothesized that a spleen may modulate humoral responses and serve as a preferential site for afucosylated IgG responses, which potentially play a role in immune thrombocytopenia (ITP) pathogenesis. To determine the role of the spleen in IgG-Fc glycosylation, we performed IgG subclass-specific liquid chromatography–mass spectrometry (LC–MS) analysis of Fc glycosylation in a large cohort of individuals splenectomized due to trauma, due to ITP, or spherocytosis. IgG-Fc fucosylation was consistently increased after splenectomy, while no effects for IgG-Fc galactosylation and sialylation were observed. An increase in IgG1- and IgG2/3-Fc fucosylation level upon splenectomy has been reported here for the first time, suggesting that immune responses occurring in the spleen may be particularly prone to generate afucosylated IgG responses. Surprisingly, the level of total IgG-Fc fucosylation was decreased in ITP patients compared to healthy controls. Overall, our results suggest a yet unrecognized role of the spleen in either the induction or maintenance of afucosylated IgG responses by B cells.


2007 ◽  
Vol 10 (04) ◽  
pp. 495-503 ◽  
Author(s):  
XIA WANG ◽  
XINYU SONG

This article proposes a mathematical model which has been used to investigate the importance of lytic and non-lytic immune responses for the control of viral infections. By means of Lyapunov functions, the global properties of the model are obtained. The virus is cleared if the basic reproduction number R0 ≤ 1 and the virus persists in the host if R0 > 1. Furthermore, if R0 > 1 and other conditions hold, the immune-free equilibrium E0 is globally asymptotically stable. The equilibrium E1 exists and is globally asymptotically stale if the CTL immune response reproductive number R1 < 1 and the antibody immune response reproductive number R2 > 1. The equilibrium E2 exists and is globally asymptotically stable if R1 > 1 and R2 < 1. Finally, the endemic equilibrium E3 exists and is globally asymptotically stable if R1 > 1 and R2 > 1.


2017 ◽  
Author(s):  
Van Kinh Nguyen ◽  
Esteban A. Hernandez-Vargas

AbstractIn recent years, mathematical modeling approaches have played a central role to understand and to quantify mechanisms in different viral infectious diseases. In this approach, biological-based hypotheses are expressed via mathematical relations and then tested based on empirical data. The simulation results can be used to either identify underlying mechanisms, provide predictions on infection outcomes, or evaluate the efficacy of a treatment.Conducting parameter estimation for mathematical models is not an easy task. Here we detail an approach to conduct parameter estimation and to evaluate the results using the free software R. The method is applicable to influenza virus dynamics at different complexity levels, widening experimentalists capabilities in understanding their data. The parameter estimation approach presented here can be also applied to other viral infections or biological applications.


2007 ◽  
Vol 81 (18) ◽  
pp. 10101-10112 ◽  
Author(s):  
P. J. Holst ◽  
C. Orskov ◽  
K. Qvortrup ◽  
J. P. Christensen ◽  
A. R. Thomsen

ABSTRACT CCR5 and CXCR3 are important molecules in regulating the migration of activated lymphocytes. Thus, the majority of tissue-infiltrating T cells found in the context of autoimmune conditions and viral infections express CCR5 and CXCR3, and the principal chemokine ligands are expressed within inflamed tissues. Accordingly, intervention studies have pointed to nonredundant roles of these receptors in models of allograft rejection, viral infection, and autoimmunity. In spite of this, considerable controversy exists, with many studies failing to support a role for CCR5 or CXCR3 in disease pathogenesis. One possible explanation is that different chemokine receptors may take over in the absence of any individual receptor, thus rendering individual receptors redundant. We have attempted to address this issue by analyzing CCR5−/−, CXCR3−/−, and CCR5/CXCR3−/− mice with regard to virus-induced liver inflammation, generation and recruitment of effector cells, virus control, and immunopathology. Our results indicate that CCR5 and CXCR3 are largely dispensable for tissue infiltration and virus control. In contrast, the T-cell response is accelerated in CCR5−/− and CCR5/CXCR3−/− mice and the absence of CCR5 is associated with the induction of CD8+ T-cell-mediated immunopathology consisting of marked hepatic microvesicular steatosis.


2018 ◽  
Author(s):  
Laura Matrajt ◽  
M. Elizabeth Halloran ◽  
Rustom Antia

Live-attenuated vaccines are usually highly effective against many acute viral infections. However, the effective- ness of the live attenuated influenza vaccine (LAIV) can vary widely, ranging from 0% effectiveness in some studies done in the United States to 50% in studies done in Europe. The reasons for these discrepancies remain largely unclear. In this paper we use mathematical models to explore how the efficacy of LAIV is affected by the degree of mismatch with the currently circulating influenza strain and interference with pre-existing immunity. The model incorporates two key antigenic distances - the distance between pre-existing immunity and the currently circulating strain as well as the LAIV strain. Our models show that a LAIV that is matched with the currently circulating strain is likely to have only modest efficacy. Our results suggest that the efficacy of the vaccine would be increased (optimized) if, rather than being matched to the circulating strain, it is antigenically slightly further from pre-existing immunity compared with the circulating strain. The models also suggest two regimes in which LAIV that is matched to circulating strains may provide effective protection. The first is in children before they have built immunity from circulating strains. The second is in response to novel strains (such as antigenic shifts) which are at substantial antigenic distance from previously circulating strains. Our models provide an explanation for the variation in vaccine effectiveness, both between children and adults as well as between studies of vaccine effectiveness observed during the 2014-15 influenza season in different countries.


2016 ◽  
Vol 3 (2) ◽  
pp. 150661 ◽  
Author(s):  
Shaun R. Stipp ◽  
Abdon Iniguez ◽  
Frederic Wan ◽  
Dominik Wodarz

CD8 T cell or cytotoxic T lymphocyte (CTL) responses are an important branch of the immune system in the fight against viral infections. The dynamics of anti-viral CTL responses have been characterized in some detail, both experimentally and with mathematical models. An interesting experimental observation concerns the timing of CTL responses. A recent study reported that in pneumonia virus of mice the effector CTL tended to arrive in the lung only after maximal virus loads had been achieved, an observation that seems at first counterintuitive because prevention of pathology would require earlier CTL-mediated activity. A delay in CTL-mediated effector activity has also been quoted as a possible explanation for the difficulties associated with CTL-based vaccines. This paper uses mathematical models to show that in specific parameter regimes, delayed CTL effector activity can be advantageous for the host in the sense that it can increase the chances of virus clearance. The increased ability of the CTL to clear the infection, however, is predicted to come at the cost of acute pathology, giving rise to a trade-off, which is discussed in the light of evolutionary processes. This work provides a theoretical basis for understanding the described experimental observations.


Vaccines ◽  
2019 ◽  
Vol 7 (3) ◽  
pp. 103 ◽  
Author(s):  
Sai Priya Anand ◽  
Andrés Finzi

Antibodies play a crucial role in host defense against viruses, both by preventing infection and by controlling viral replication. Besides their capacity to neutralize viruses, antibodies also exert their antiviral effects by crystallizable fragment (Fc)-mediated effector mechanisms. This involves a bridge between innate and adaptive immune systems, wherein antibodies form immune complexes that drive numerous innate immune effector functions, including antibody-dependent cellular cytotoxicity, antibody-dependent complement-mediated lysis, and antibody-dependent phagocytosis. Here, we review certain mechanisms that modulate these antibody-mediated effector functions against virally infected cells, such as viral glycoprotein shedding, viral glycoprotein internalization, antibody cooperativity, and antibody glycosylation. These mechanisms can either protect viral replication or enhance infected cell clearance. Here we discuss the importance of these understudied factors in modulating Fc-mediated effector functions.


2021 ◽  
Author(s):  
Hannah D. Stacey ◽  
Diana Golubeva ◽  
Alyssa Posca ◽  
Jann C. Ang ◽  
Kyle E. Novakowski ◽  
...  

ABSTRACTIgA is the second most abundant antibody present in circulation and is enriched at mucosal surfaces. As such, IgA plays a key role in protection against a variety of mucosal pathogens, including viruses. In addition to neutralizing viruses directly, IgA can also stimulate Fc-dependent effector functions via engagement of Fc alpha receptors (FcαRI) expressed on the surface of certain immune effector cells. Neutrophils are the most abundant leukocyte, express FcαRI, and are often the first to respond to sites of injury and infection. Here, we describe a novel function for IgA:virus immune complexes (ICs) during viral infections. We show that IgA:virus ICs potentiate NETosis – the programmed cell death pathway through which neutrophils release neutrophil extracellular traps (NETs). Mechanistically, IgA:virus ICs potentiated a suicidal NETosis pathway via engagement of FcαRI on neutrophils through a toll-like receptor (TLR)-independent, NADPH oxidase complex-dependent pathway. NETs also were capable of trapping and inactivating viruses, consistent with an antiviral function.


2021 ◽  
Vol 118 (27) ◽  
pp. e2101497118
Author(s):  
Hannah D. Stacey ◽  
Diana Golubeva ◽  
Alyssa Posca ◽  
Jann C. Ang ◽  
Kyle E. Novakowski ◽  
...  

IgA is the second most abundant antibody present in circulation and is enriched at mucosal surfaces. As such, IgA plays a key role in protection against a variety of mucosal pathogens including viruses. In addition to neutralizing viruses directly, IgA can also stimulate Fc-dependent effector functions via engagement of Fc alpha receptors (Fc-αRI) expressed on the surface of certain immune effector cells. Neutrophils are the most abundant leukocyte, express Fc-αRI, and are often the first to respond to sites of injury and infection. Here, we describe a function for IgA–virus immune complexes (ICs) during viral infections. We show that IgA–virus ICs potentiate NETosis—the programmed cell-death pathway through which neutrophils release neutrophil extracellular traps (NETs). Mechanistically, IgA–virus ICs potentiated a suicidal NETosis pathway via engagement of Fc-αRI on neutrophils through a toll-like receptor–independent, NADPH oxidase complex–dependent pathway. NETs also were capable of trapping and inactivating viruses, consistent with an antiviral function.


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