scholarly journals Faster growth with shorter antigens explains a VSG hierarchy during African trypanosome infections: a feint attack by parasites

2017 ◽  
Author(s):  
Dianbo Liu ◽  
Luca Albergante ◽  
David Horn ◽  
Timothy Newman
Keyword(s):  
Immune Response ◽  
Trypanosoma Brucei ◽  
Temporal Distribution ◽  
Inverse Correlation ◽  
Host Immune Response ◽  
Surface Proteins ◽  
Host Immune System ◽  
Differential Growth ◽  
African Trypanosome

AbstractThe parasitic African trypanosome, Trypanosoma brucei, evades the adaptive host immune response by a process of antigenic variation that involves the clonal switching of variant surface glycoproteins (VSGs). The VSGs that periodically come to dominate in vivo display a hierarchy, but how this hierarchy arises is not well-understood. Combining publicly available genetic data with mathematical modelling, we report a VSG-length-dependent hierarchical timing of clonal VSG dominance in a mouse model, revealing an inverse correlation between VSG length and trypanosome growth-rate. Our analysis indicates that, among parasites switching to new VSGs, those expressing shorter VSGs preferentially accumulate to a detectable level that is sufficient to trigger an effective immune response. Subsequent elimination of faster-growing parasites then allows slower parasites with longer VSGs to accumulate. This interaction between the host and parasite is able by itself to explain the temporal distribution of VSGs observed in vivo. Thus, our findings reveal a length-dependent hierarchy that operates during T. brucei infection, representing a ‘feint attack’ diversion tactic utilised during infection by these persistent parasites to out-maneuver the host immune system.Significance StatementThe protozoan parasite Trypanosoma brucei causes devastating and lethal diseases in humans and livestock. This parasite continuously evades the host adaptive immune response by drawing on a library of variant surface proteins but the mechanisms determining the timing of surface protein – host interactions are not understood. We report a simple mechanism, based on differential growth of parasites with surface proteins of different lengths, which can explain the hierarchy of variants over time. This allows parasites to evade host immune responses for extended timeframes using limited cohorts of surface proteins. We liken this strategy to a military ‘feint attack’, that enhances the parasites ability to evade the host immune response. A similar mechanism may also operate in other important pathogens.

scholarly journals Modulation of the Host Immune Response by Schistosome Egg-Secreted Proteins Is a Critical Avenue of Host–Parasite Communication

Pathogens ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 863
Author(s):  
Jack P. Carson ◽  
Geoffrey N. Gobert
Keyword(s):  
Immune Response ◽  
Current Knowledge ◽  
Host Immune Response ◽  
Egg Laying ◽  
Host Cells ◽  
Future Application ◽  
Mammalian Host ◽  
Immunomodulatory Activity ◽  
Host Immune System

During a schistosome infection, the interactions that occur between the mammalian host and the parasite change rapidly once egg laying begins. Both juvenile and adult schistosomes adapt to indefinitely avoid the host immune system. In contrast, the survival of eggs relies on quickly traversing from the host. Following the commencement of egg laying, the host immune response undergoes a shift from a type 1 helper (Th1) inflammatory response to a type 2 helper (Th2) granulomatous response. This change is driven by immunomodulatory proteins within the egg excretory/secretory products (ESPs), which interact with host cells and alter their behaviour to promote egg translocation. However, in parallel, these ESPs also provoke the development of chronic schistosomiasis pathology. Recent studies using high-throughput proteomics have begun to characterise the components of schistosome egg ESPs, particularly those of Schistosoma mansoni, S. japonicum and S. haematobium. Future application of this knowledge may lead to the identification of proteins with novel immunomodulatory activity or pathological importance. However, efforts in this area are limited by a lack of in situ or in vivo functional characterisation of these proteins. This review will highlight the current knowledge of the content and demonstrated functions of schistosome egg ESPs.

scholarly journals The Brilliance of Borrelia: Mechanisms of Host Immune Evasion by Lyme Disease-Causing Spirochetes

Pathogens ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 281
Author(s):  
Cassidy Anderson ◽  
Catherine A. Brissette
Keyword(s):  
Immune Response ◽  
Lyme Disease ◽  
Immune Evasion ◽  
Host Immune Response ◽  
Surface Proteins ◽  
Borrelia Burgdorferi Sensu Lato ◽  
Adaptive Responses ◽  
Tick Saliva ◽  
Vector Borne ◽  
Antimicrobial Peptide Resistance

Lyme disease (LD) has become the most common vector-borne illness in the northern hemisphere. The causative agent, Borrelia burgdorferi sensu lato, is capable of establishing a persistent infection within the host. This is despite the activation of both the innate and adaptive immune responses. B. burgdorferi utilizes several immune evasion tactics ranging from the regulation of surface proteins, tick saliva, antimicrobial peptide resistance, and the disabling of the germinal center. This review aims to cover the various methods by which B. burgdorferi evades detection and destruction by the host immune response, examining both the innate and adaptive responses. By understanding the methods employed by B. burgdorferi to evade the host immune response, we gain a deeper knowledge of B. burgdorferi pathogenesis and Lyme disease, and gain insight into how to create novel, effective treatments.

scholarly journals Leishmania donovani Secretory Mevalonate Kinase Regulates Host Immune Response and Facilitates Phagocytosis

2021 ◽  
Vol 11 ◽  
Author(s):  
Tanvir Bamra ◽  
Taj Shafi ◽  
Sushmita Das ◽  
Manjay Kumar ◽  
Manas Ranjan Dikhit ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune System ◽  
Leishmania Donovani ◽  
Indian Subcontinent ◽  
Parasite Burden ◽  
Host Immune Response ◽  
Host Cells ◽  
Interleukin 4 ◽  
Host Immune System ◽  
Mevalonate Kinase

Summary StatementLeishmania secretes over 151 proteins during in vitro cultivation. Cellular functions of one such novel protein: mevalonate kinase is discussed here; signifying its importance in Leishmania infection.Visceral Leishmaniasis is a persistent infection, caused by Leishmania donovani in Indian subcontinent. This persistence is partly due to phagocytosis and evasion of host immune response. The underlying mechanism involves secretory proteins of Leishmania parasite; however, related studies are meagre. We have identified a novel secretory Leishmania donovani glycoprotein, Mevalonate kinase (MVK), and shown its importance in parasite internalization and immuno-modulation. In our studies, MVK was found to be secreted maximum after 1 h temperature stress at 37°C. Its secretion was increased by 6.5-fold in phagolysosome-like condition (pH ~5.5, 37°C) than at pH ~7.4 and 25°C. Treatment with MVK modulated host immune system by inducing interleukin-10 and interleukin-4 secretion, suppressing host’s ability to kill the parasite. Peripheral blood mononuclear cell (PBMC)-derived macrophages infected with mevalonate kinase-overexpressing parasites showed an increase in intracellular parasite burden in comparison to infection with vector control parasites. Mechanism behind the increase in phagocytosis and immunosuppression was found to be phosphorylation of mitogen-activated protein (MAP) kinase pathway protein, Extracellular signal-regulated kinases-1/2, and actin scaffold protein, cortactin. Thus, we conclude that Leishmania donovani Mevalonate kinase aids in parasite engulfment and subvert the immune system by interfering with signal transduction pathways in host cells, which causes suppression of the protective response and facilitates their persistence in the host. Our work elucidates the involvement of Leishmania in the process of phagocytosis which is thought to be dependent largely on macrophages and contributes towards better understanding of host pathogen interactions.

Conditioning Intensity and Dendritic Cell (DC) Activation: Implications for GVHD Control Using DC Depleting Antibodies.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3112-3112
Author(s):  
Brie E. Turner ◽  
Melinda Christensen ◽  
Janusz Lange ◽  
Ann-Marie Burns ◽  
Derek N.J. Hart ◽  
...  
Keyword(s):  
Immune Response ◽  
Effective Means ◽  
Haematopoietic Stem Cell ◽  
Antibody Concentration ◽  
Host Immune System ◽  
Widespread Application ◽  
Conditioning Regimens ◽  
Control Disease ◽  
Conditioning Intensity

Abstract Graft versus Host Disease (GVHD) and treatment related mortality (TRM) are the major limitations to the widespread application of allogeneic haematopoietic stem cell transplantation (HSCT) for haematological and non-haematological malignancies. Dendritic cells (DC) as the key initiators and directors of the immune response are central to allogeneic transplant interactions. Preparative conventional conditioning (CC) regimens aim to control disease and ablate the host immune response to facilitate normal haematopoietic reconstitution. The conditioning also unleashes a cytokine storm that activates the residual host immune system, driving host DC and donor T cell interactions that result in GVHD. Reducing the intensity of conditioning (RIC) regimens maintains immune anti-leukaemic activity of T replete HSCT, reduces TRM and delays the onset of GVHD, but the overall incidence of GVHD is unchanged. We hypothesise that this is due to increased persistence of host DC. We propose that strategic administration of DC depleting antibodies could be an effective means to control GVHD. Whilst there is some information on the effects of CC on DC; we have shown that mature plasmacytoid (p) DC are increased in mouse spleen after conditioning by radiation, there is no information on the effects of RIC on DC. We have established murine models of conditioning (CC = Cyclophosphamide [CY] + 800cGy and RIC = Fludarabine [FLU] + CY + 200cGy). The effects on DC numbers, activation and subset composition (myeloid (m) DC and DC), cytokine and systemic endotoxin levels were studied on each day of the conditioning regimens in the absence of HSCT. Mice receiving CC have a significantly higher percentage of DC which are pDC compared to RIC (p<0.001) which results in a decrease in the overall percentage of mDC. However, mice that received RIC have significantly higher absolute numbers of host pDC than CC mice. Preliminary data shows no difference in endotoxin levels in mice receiving RIC or CC without HSCT. However, there may be a transient increase in endotoxin levels in mice after 2 FLU injections (p=0.12). No such increase was seen after CC. There were significantly higher levels of TNF-α (p=0.02) and IL1-β (p=0.03) in mice receiving RIC rather than CC without HSCT. The higher absolute numbers of DC, altered subset ratio and cytokine production appears to account for the delayed onset of GVHD in RIC transplant recipients. Intra-peritoneal (ip) injection of N418, a monoclonal antibody to mouse leukocyte integrin CD11c depleted murine DC in vivo. Preliminary experiments show elimination of 50% of DC after injection of N418 (500mg). Subsequent experiments show that 1mg of N418 is sufficient to significantly delay, but not prevent, GVHD in a full MHC mismatched model of HSCT (p=0.025). The action of N418 is specific, as DC depletion was not seen in mice treated with 1 mg hamster Ig. Together, these observations suggest that increasing antibody concentration and prolonged administration may be required to prevent GVHD. The successful application of DC depletion to control GVHD will improve the safety of HSCT for patients with leukaemia.

Unravelling some mysteries of porcine respiratory and reproductive syndrome virus (PRRSV) infections: new insights from modelling studies

2009 ◽  
Vol 2009 ◽  
pp. 30-30
Author(s):  
A Doeschl-Wilson ◽  
I Kyriazakis ◽  
L Galina-Pantoja
Keyword(s):  
Immune Response ◽  
Host Immune Response ◽  
Growing Pigs ◽  
Modelling Studies ◽  
Porcine Respiratory ◽  
Insight Into

Porcine reproductive and respiratory syndrome (PRRS) is an endemic pig disease in most European countries, causing respiratory distress, fever and growth reductions in growing pigs and increased litter mortality in sows. The disease is characterised by exceptionally long-term viral persistence within the host, a weak innate host immune response and delayed adaptive host immune response, and large between animal variation in the immune response (Murtaugh et al., 2004). Although numerous in-vitro and in-vivo studies produced valid insight into the fine details of the virus dynamics and its interaction with the host’s immune response, several fundamental questions concerning the role of diverse immune components and host genetics remain unanswered. In this study mathematical models were developed to investigate the role of diverse processes caused by the virus or the immune response on the infection characteristics.

Comparative in vivo infection models yield insights on early host immune response to Campylobacter in chickens

2008 ◽  
Vol 61 (2) ◽  
pp. 101-110 ◽  
Author(s):  
Kieran G. Meade ◽  
Fernando Narciandi ◽  
Sarah Cahalane ◽  
Carla Reiman ◽  
Brenda Allan ◽  
...  
Keyword(s):  
Immune Response ◽  
Host Immune Response ◽  
Infection Models

scholarly journals The Bacterial Second Messenger Cyclic di-GMP Regulates Brucella Pathogenesis and Leads to Altered Host Immune Response

2016 ◽  
Vol 84 (12) ◽  
pp. 3458-3470 ◽  
Author(s):  
Mike Khan ◽  
Jerome S. Harms ◽  
Fernanda M. Marim ◽  
Leah Armon ◽  
Cherisse L. Hall ◽  
...  
Keyword(s):  
Immune Response ◽  
Second Messenger ◽  
Host Immune Response ◽  
Vital Role ◽  
Host Cells ◽  
Content Type ◽  
Type Iv

Brucella species are facultative intracellular bacteria that cause brucellosis, a chronic debilitating disease significantly impacting global health and prosperity. Much remains to be learned about how Brucella spp. succeed in sabotaging immune host cells and how Brucella spp. respond to environmental challenges. Multiple types of bacteria employ the prokaryotic second messenger cyclic di-GMP (c-di-GMP) to coordinate responses to shifting environments. To determine the role of c-di-GMP in Brucella physiology and in shaping host- Brucella interactions, we utilized c-di-GMP regulatory enzyme deletion mutants. Our results show that a Δ bpdA phosphodiesterase mutant producing excess c-di-GMP displays marked attenuation in vitro and in vivo during later infections. Although c-di-GMP is known to stimulate the innate sensor STING, surprisingly, the Δ bpdA mutant induced a weaker host immune response than did wild-type Brucella or the low-c-di-GMP guanylate cyclase Δ cgsB mutant. Proteomics analysis revealed that c-di-GMP regulates several processes critical for virulence, including cell wall and biofilm formation, nutrient acquisition, and the type IV secretion system. Finally, Δ bpdA mutants exhibited altered morphology and were hypersensitive to nutrient-limiting conditions. In summary, our results indicate a vital role for c-di-GMP in allowing Brucella to successfully navigate stressful and shifting environments to establish intracellular infection.

scholarly journals Modelling The Effect of MUC1 on Influenza Virus Infection Kinetics and Macrophage Dynamics

2021 ◽  
Author(s):  
Ke Li ◽  
Pengxing Cao ◽  
James M. McCaw
Keyword(s):  
Immune Response ◽  
Influenza Virus ◽  
Viral Replication ◽  
Influenza Infection ◽  
Influenza Virus Infection ◽  
Host Immune Response ◽  
Viral Control ◽  
Macrophage Populations ◽  
Influenza Viral Infection

AbstractMUC1 belongs to the family of cell surface (cs-) mucins. Experimental evidence indicates that its presence reduces in vivo influenza viral infection severity. However, the mechanisms by which MUC1 influences viral dynamics and the host immune response are not yet well understood, limiting our ability to predict the efficacy of potential treatments that target MUC1. To address this limitation, we utilize available in vivo kinetic data for both virus and macrophage populations in wildtype and MUC1 knockout mice. We apply two mathematical models of within-host influenza dynamics to this data. The models differ in how they categorise the mechanisms of viral control. Both models provide evidence that MUC1 reduces the susceptibility of epithelial cells to influenza virus and regulates macrophage recruitment. Furthermore, we predict and compare some key infection-related quantities between the two mice groups. We find that MUC1 significantly reduces the basic reproduction number of viral replication as well as the number of cumulative macrophages but has little impact on the cumulative viral load. Our analyses suggest that the viral replication rate in the early stages of infection influences the kinetics of the host immune response, with consequences for infection outcomes, such as severity. We also show that MUC1 plays a strong anti-inflammatory role in the regulation of the host immune response. This study improves our understanding of the dynamic role of MUC1 against influenza infection and may support the development of novel antiviral treatments and immunomodulators that target MUC1.

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