scholarly journals Mapping immune variation and var gene switching in naive hosts infected with Plasmodium falciparum

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Kathryn Milne ◽  
Alasdair Ivens ◽  
Adam J Reid ◽  
Magda E Lotkowska ◽  
Aine O'Toole ◽  
...  
Keyword(s):  
Host Response ◽  
Severe Disease ◽  
Myeloid Cell ◽  
Relative Contribution ◽  
Variant Surface Antigen ◽  
Controlled Human Malaria Infection ◽  
Cell Suppression ◽  
Induced Changes ◽  
Gene Switching ◽  
Var Gene

Falciparum malaria is clinically heterogeneous and the relative contribution of parasite and host in shaping disease severity remains unclear. We explored the interaction between inflammation and parasite variant surface antigen (VSA) expression, asking whether this relationship underpins the variation observed in controlled human malaria infection (CHMI). We uncovered marked heterogeneity in the host response to blood challenge; some volunteers remained quiescent, others triggered interferon-stimulated inflammation and some showed transcriptional evidence of myeloid cell suppression. Significantly, only inflammatory volunteers experienced hallmark symptoms of malaria. When we tracked temporal changes in parasite VSA expression to ask whether variants associated with severe disease rapidly expand in naive hosts, we found no transcriptional evidence to support this hypothesis. These data indicate that parasite variants that dominate severe malaria do not have an intrinsic growth or survival advantage; instead, they presumably rely upon infection-induced changes in their within-host environment for selection.

scholarly journals Diverse outcomes of controlled human malaria infection originate from host-intrinsic immune variation and not var gene switching

2020 ◽  
Author(s):  
Kathryn Milne ◽  
Alasdair Ivens ◽  
Adam J. Reid ◽  
Magda E. Lotkowska ◽  
Áine O'Toole ◽  
...  
Keyword(s):  
Malaria Infection ◽  
Severe Disease ◽  
Myeloid Cell ◽  
Current Theory ◽  
Human Malaria ◽  
Relative Contribution ◽  
Gene Profiles ◽  
Controlled Human Malaria Infection ◽  
Gene Switching ◽  
Selection Of

Falciparum malaria is clinically heterogeneous and the relative contribution of parasite and host in shaping disease severity remains unclear. We explored the interaction between inflammation and parasite variant surface antigen (VSA) expression, asking whether this relationship underpins the variation observed in controlled human malaria infection (CHMI). We uncovered marked heterogeneity in the response of naive hosts to blood challenge; some volunteers remained quiescent, others triggered interferon-stimulated inflammation and some showed transcriptional evidence of myeloid cell suppression. Significantly, only inflammatory volunteers experienced hallmark symptoms of malaria. When we tracked temporal changes in parasite VSA expression to ask whether variants associated with severe disease preferentially expand in naive hosts (as predicted by current theory) we found that var gene profiles were unchanged after 10-days of infection. The diverse outcomes of CHMI therefore depend upon human immune variation and there is no evidence for switching or selection of var genes in naive hosts.

scholarly journals De-Coding the Contributions of the Viral RNAs to Alphaviral Pathogenesis

Pathogens ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 771
Author(s):  
Autumn T. LaPointe ◽  
Kevin J. Sokoloski
Keyword(s):  
Host Response ◽  
Severe Disease ◽  
Review Article ◽  
Structural Proteins ◽  
Virulence Determinants ◽  
Healthy Individuals ◽  
Viral Rnas ◽  
Positive Sense ◽  
Identification And Characterization

Alphaviruses are positive-sense RNA arboviruses that are capable of causing severe disease in otherwise healthy individuals. There are many aspects of viral infection that determine pathogenesis and major efforts regarding the identification and characterization of virulence determinants have largely focused on the roles of the nonstructural and structural proteins. Nonetheless, the viral RNAs of the alphaviruses themselves play important roles in regard to virulence and pathogenesis. In particular, many sequences and secondary structures within the viral RNAs play an important part in the development of disease and may be considered important determinants of virulence. In this review article, we summarize the known RNA-based virulence traits and host:RNA interactions that influence alphaviral pathogenesis for each of the viral RNA species produced during infection. Overall, the viral RNAs produced during infection are important contributors to alphaviral pathogenesis and more research is needed to fully understand how each RNA species impacts the host response to infection as well as the development of disease.

Feedback-Induced Variations of Distribution in a Representative Gene Model

2015 ◽  
Vol 25 (07) ◽  
pp. 1540008
Author(s):  
Peijiang Liu ◽  
Zhanjiang Yuan ◽  
Lifang Huang ◽  
Tianshou Zhou
Keyword(s):  
Gene Expression ◽  
Power Law ◽  
Positive Feedback ◽  
Bimodal Distribution ◽  
Stochastic Bifurcation ◽  
Protein Distribution ◽  
Identical Cell ◽  
Induced Changes ◽  
Gene Switching ◽  
Cell To Cell Variability

Gene expression is inherently noisy, implying that the number of mRNAs or proteins is not invariant rather than follows a distribution. This distribution can not only provide the exact information on the dynamics of gene expression but also describe cell-to-cell variability in a genetically identical cell population. Here, we systematically investigate a two-state model of gene expression, a model paradigm used to study expression dynamics, focusing on the effect of feedback on the type of mRNA or protein distribution. If there is no feedback, then the distribution may be bimodal, power-law tailed, or Poisson-like, depending on gene switching rates. However, we find that feedback can tune or change the type of the distribution in each case and tends to unimodalize the distribution as its strength increases. Specifically, positive feedback can change not only a power-law tailed distribution into a bimodal or Poisson-like distribution but also a bimodal distribution into a Poisson-like distribution (implying that stochastic bifurcation can take place). In addition, it can make a Poisson-like distribution become more peaked but does not change the type of this distribution. In contrast to positive feedback, negative feedback has less influence on the shape of the distributions except for the bimodal case. In all cases, the noise-feedback curve used extensively in previous studies cannot well reflect the feedback-induced changes in the shape of distributions. Feedback-induced variations in distribution would be important for cell survival in fluctuating environments.

Host response to cytoadherence in Plasmodium falciparum

2008 ◽  
Vol 36 (2) ◽  
pp. 221-228 ◽  
Author(s):  
Srabasti J. Chakravorty ◽  
Katie R. Hughes ◽  
Alister G. Craig
Keyword(s):  
Plasmodium Falciparum ◽  
Tumour Necrosis ◽  
Host Response ◽  
Severe Disease ◽  
Signalling Pathways ◽  
Malarial Infection ◽  
Extensive Information ◽  
Adhesive Interactions ◽  
Necrosis Factor ◽  
Tnf Tumour Necrosis Factor

Cytoadherence of PRBCs (Plasmodium falciparum-infected red blood cells) to host endothelium has been associated with pathology in severe malaria, but, despite extensive information on the primary processes involved in the adhesive interactions, the mechanisms underlying the disease are poorly understood. Endothelial cells have the ability to mobilize immune and pro-adhesive responses when exposed to both PRBCs and TNF (tumour necrosis factor). In addition, there is also an up-regulation by PRBCs and TNF and a concurrent down-regulation of a range of genes involved in inflammation and cell death, by PRBCs and TNF. We propose that the balance between positive and negative regulation will contribute to endothelial pathology during malarial infection. Apposition of PRBCs has been shown by a number of groups to activate signalling pathways. This is dependent, at least in part, on the cytoadherence characteristics of the invading isolate, such that the avidity of the PRBC for the receptor on host endothelium is proportional to the level of activation of the signalling pathways. An understanding of the post-adhesive processes produced by cytoadherence may help us to understand the variable pathology seen in malaria and to design appropriate therapies to alleviate severe disease.

scholarly journals The Plasmodium falciparum var gene switching rate, switching mechanism and patterns of parasite recrudescence described by mathematical modelling

Parasitology ◽  
2002 ◽  
Vol 124 (3) ◽  
pp. 225-235 ◽  
Author(s):  
S. PAGET-MCNICOL ◽  
M. GATTON ◽  
I. HASTINGS ◽  
A. SAUL
Keyword(s):  
Plasmodium Falciparum ◽  
Chronic Infection ◽  
Malaria Parasite ◽  
Gene Repertoire ◽  
Switching Rate ◽  
Specific Immunity ◽  
Parasite Survival ◽  
Gene Switching ◽  
Variant Antigen ◽  
Var Gene

Recrudescing Plasmodium falciparum parasitaemia is attributed to the switching of PfEMP1, a variant antigen family encoded by the var gene repertoire, and the host's immune response. We have developed a mathematical model which incorporates var gene switching, and variant specific, non-variant specific and non-specific immunity. By conducting a sensitivity analysis of the model we have defined the parameter limits which produce chronic and recrudescing infections. We explore 3 switching mechanisms: ordered, random and uncoupled switching. We show that if var genes switch on and off independently at variable rates through the repertoire a chronic clinical infection is predicted. The fastest switching-on rate that produces a chronic infection is 0·03% per generation. The model predicts that non-variant specific immunity plays an important role in reducing disease severity. This work illustrates the complex relationship between the malaria parasite and its host and shows that var gene switching at rates substantially slower than 2% are essential for parasite survival.

scholarly journals Pulmonary insults exacerbate susceptibility to oral Listeria monocytogenes infection through the production of IL-10 by NK cells

2021 ◽  
Vol 17 (4) ◽  
pp. e1009531
Author(s):  
Nikki Bortell ◽  
Elizabeth R. Aguilera ◽  
Laurel L. Lenz
Keyword(s):  
Listeria Monocytogenes ◽  
Nk Cells ◽  
Severe Disease ◽  
Bacterial Pathogen ◽  
Myeloid Cell ◽  
The Elderly ◽  
Interleukin 10 ◽  
Human Populations ◽  
Phagocytic Capacity ◽  
Increase Disease Susceptibility

Most individuals who consume foods contaminated with the bacterial pathogen Listeria monocytogenes (Lm) develop mild symptoms, while others are susceptible to life-threatening systemic infections (listeriosis). Although it is known that the risk of severe disease is increased in certain human populations, including the elderly, it remains unclear why others who consume contaminated food develop listeriosis. Here, we used a murine model to discover that pulmonary coinfections can impair the host’s ability to adequately control and eradicate systemic Lm that cross from the intestines to the bloodstream. We found that the resistance of mice to oral Lm infection was dramatically reduced by coinfection with Streptococcus pneumoniae (Spn), a bacterium that colonizes the respiratory tract and can also cause severe infections in the elderly. Exposure to Spn or microbial products, including a recombinant Lm protein (L1S) and lipopolysaccharide (LPS), rendered otherwise resistant hosts susceptible to severe systemic Lm infection. In addition, we show that this increase in susceptibility was dependent on an increase in the production of interleukin-10 (IL-10) from Ncr1+ cells, including Natural Killer (NK) cells. Lastly, the ability of Ncr1+ derived IL-10 to increase disease susceptibility correlated with a dampening of both myeloid cell accumulation and myeloid cell phagocytic capacity in infected tissues. These data suggest that efforts to minimize inflammation in response to an insult at the respiratory mucosa render the host more susceptible to infections by Lm and possibly other pathogens that access the oral mucosa.

scholarly journals Clinical Characterization of Host Response to Simian Hemorrhagic Fever Virus Infection in Permissive and Refractory Hosts: A Model for Determining Mechanisms of VHF Pathogenesis

2018 ◽  
Author(s):  
Joseph P. Cornish ◽  
Ian N. Moore ◽  
Donna L. Perry ◽  
Abigail Lara ◽  
Mahnaz Minai ◽  
...  
Keyword(s):  
Rhesus Monkeys ◽  
Host Response ◽  
Severe Disease ◽  
Hemorrhagic Fever ◽  
Fever Virus ◽  
Host Responses ◽  
Viral Hemorrhagic Fever ◽  
Simian Hemorrhagic Fever Virus ◽  
Patas Monkeys ◽  
Hemorrhagic Fever Virus

ABSTRACTSimian hemorrhagic fever virus (SHFV) causes a fulminant and typically lethal viral hemorrhagic fever (VHF) in macaques (Cercopithecinae: Macaca spp.) but causes subclinical infections in patas monkeys (Cercopithecinae: Erythrocebus patas). This difference in disease course offers a unique opportunity to compare host-responses to infection by a VHF-causing virus in biologically similar susceptible and refractory animals. Patas and rhesus monkeys were inoculated side-by-side with SHFV. In contrast to the severe disease observed in rhesus monkeys, patas monkeys developed a limited clinical disease characterized by changes in complete blood counts, serum chemistries, and development of lymphadenopathy. Viremia was measurable 2 days after exposure and its duration varied by species. Infectious virus was detected in terminal tissues of both patas and rhesus monkeys. Varying degrees of overlap in changes in serum concentrations of IFN-γ, MCP-1, and IL-6 were observed between patas and rhesus monkeys, suggesting the presence of common and species-specific cytokine responses to infection. Similarly, quantitative immunohistochemistry of terminal livers and whole blood flow cytometry revealed varying degrees of overlap in changes in macrophages, natural killer cells, and T-cells. The unexpected degree of overlap in host-response suggests that relatively small subsets of a host’s response to infection may be responsible for driving pathogenesis that results in a hemorrhagic fever. Furthermore, comparative SHFV infection in patas and rhesus monkeys offers an experimental model to characterize host-response mechanisms associated with viral hemorrhagic fever and evaluate pan-viral hemorrhagic fever countermeasures.IMPORTANCEHost-response mechanisms involved in pathogenesis of VHFs remain poorly understood. An underlying challenge is separating beneficial, inconsequential, and detrimental host-responses during infection. The comparison of host-responses to infection with the same virus in biologically similar animals that have drastically different disease manifestations allows for the identification of pathogenic mechanisms. SHFV, a surrogate virus for human VHF-causing viruses likely causes subclinical infection in African monkeys such as patas monkeys but can cause severe disease in Asian macaque monkeys. Data from the accompanying article by Buechler et al. support that infection of macaques and baboons with non-SHFV simarteviruses can establish persistent or long-term subclinical infections. Baboons, macaques, and patas monkeys are relatively closely taxonomically related (Cercopithecidae: Cercopithecinae) and therefore offer a unique opportunity to dissect how host-response differences determine disease outcome in VHFs.

scholarly journals Severe COVID-19 Recovery Is Associated with Timely Acquisition of a Myeloid Cell Immune-Regulatory Phenotype

2021 ◽  
Vol 12 ◽  
Author(s):  
Amelia C. Trombetta ◽  
Guilherme B. Farias ◽  
André M. C. Gomes ◽  
Ana Godinho-Santos ◽  
Pedro Rosmaninho ◽  
...  
Keyword(s):  
Dendritic Cell ◽  
Cell Activation ◽  
Inflammatory Responses ◽  
Severe Disease ◽  
Myeloid Cell ◽  
Cell Phenotype ◽  
Icu Patients ◽  
Icu Discharge ◽  
Dendritic Cell Subsets ◽  
Regulatory Phenotype

After more than one year since the COVID-19 outbreak, patients with severe disease still constitute the bottleneck of the pandemic management. Aberrant inflammatory responses, ranging from cytokine storm to immune-suppression, were described in COVID-19 and no treatment was demonstrated to change the prognosis significantly. Therefore, there is an urgent need for understanding the underlying pathogenic mechanisms to guide therapeutic interventions. This study was designed to assess myeloid cell activation and phenotype leading to recovery in patients surviving severe COVID-19. We evaluated longitudinally patients with COVID-19 related respiratory insufficiency, stratified according to the need of intensive care unit admission (ICU, n = 11, and No-ICU, n = 9), and age and sex matched healthy controls (HCs, n = 11), by flow cytometry and a wide array of serum inflammatory/immune-regulatory mediators. All patients featured systemic immune-regulatory myeloid cell phenotype as assessed by both unsupervised and supervised analysis of circulating monocyte and dendritic cell subsets. Specifically, we observed a reduction of CD14lowCD16+ monocytes, and reduced expression of CD80, CD86, and Slan. Moreover, mDCs, pDCs, and basophils were significantly reduced, in comparison to healthy subjects. Contemporaneously, both monocytes and DCs showed increased expression of CD163, CD204, CD206, and PD-L1 immune-regulatory markers. The expansion of M2-like monocytes was significantly higher at admission in patients featuring detectable SARS-CoV-2 plasma viral load and it was positively correlated with the levels of specific antibodies. In No-ICU patients, we observed a peak of the alterations at admission and a progressive regression to a phenotype similar to HCs at discharge. Interestingly, in ICU patients, the expression of immuno-suppressive markers progressively increased until discharge. Notably, an increase of M2-like HLA-DRhighPD-L1+ cells in CD14++CD16− monocytes and in dendritic cell subsets was observed at ICU discharge. Furthermore, IFN-γ and IL-12p40 showed a decline over time in ICU patients, while high values of IL1RA and IL-10 were maintained. In conclusion, these results support that timely acquisition of a myeloid cell immune-regulatory phenotype might contribute to recovery in severe systemic SARS-CoV-2 infection and suggest that therapeutic agents favoring an innate immune system regulatory shift may represent the best strategy to be implemented at this stage.

Adenosine-induced changes in atrial action potential: contribution of Ca and K currents

1990 ◽  
Vol 258 (4) ◽  
pp. H1070-H1078 ◽  
Author(s):  
S. Visentin ◽  
S. N. Wu ◽  
L. Belardinelli
Keyword(s):  
Action Potential ◽  
Potassium Current ◽  
Potential Contribution ◽  
Strongly Correlated ◽  
Patch Clamp Technique ◽  
Relative Contribution ◽  
Whole Cell Patch Clamp ◽  
Maximum Decrease ◽  
Induced Changes ◽  
K Currents

In this study, we examined the relative contribution of the increase in acetylcholine-regulated potassium current (IK ACh) and decrease in calcium current (ICa) to the adenosine (Ado)-induced shortening of action potential duration (APD). In isolated guinea pig atrial myocytes, membrane potentials and currents were measured by the whole cell patch-clamp technique. ICa and IK ACh were individualized by blocking the K currents with Cs+ and ICa with Cd2+. The effects of Ado on membrane potential and currents were concentration dependent. Ado (10 microM) shortened APD at 0 mV and at 90% of repolarization (APD0,90) to 7 +/- 1 and 26 +/- 6 ms from control values of 23 +/- 3 and 89 +/- 6 ms, respectively. Concomitant with the changes in APD, Ado decreased ICa from -9.2 +/- 1.3 to -6.8 +/- 10 microA/microF (26% decrease) but increased IK ACh from +3.5 +/- 0.5 to +7.8 +/- 0.8 microA/microF (123% increase). When rundown of ICa was taken into account, the maximum decrease in ICa caused by Ado was 12%. The effect of Ado on ICa and IK ACh was not altered by treatment of the cells with either Cs+ or Cd2+. The shortening of ADP0,90 strongly correlated with the increase in IK ACh but minimally with the decrease in ICa. A 22% reduction in ICa caused by lowering extracellular Ca2+ concentration ([Ca2+]o) from 3.6 to 1.8 mM was associated with an 11 and 14% shortening of APD0 and APD90, respectively. In the same myocytes an 18% decrease in ICa by 10 microM Ado reduced APD0 and APD90 by 58 and 61%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Clinical Characterization of Host Response to Simian Hemorrhagic Fever Virus Infection in Permissive and Refractory Hosts: A Model for Determining Mechanisms of VHF Pathogenesis

Viruses ◽  
2019 ◽  
Vol 11 (1) ◽  
pp. 67
Author(s):  
Joseph Cornish ◽  
Ian Moore ◽  
Donna Perry ◽  
Abigail Lara ◽  
Mahnaz Minai ◽  
...  
Keyword(s):  
Rhesus Monkeys ◽  
Host Response ◽  
Severe Disease ◽  
Hemorrhagic Fever ◽  
Fever Virus ◽  
Host Responses ◽  
Viral Hemorrhagic Fever ◽  
Simian Hemorrhagic Fever Virus ◽  
Patas Monkeys ◽  
Hemorrhagic Fever Virus

Simian hemorrhagic fever virus (SHFV) causes a fulminant and typically lethal viral hemorrhagic fever (VHF) in macaques (Cercopithecinae: Macaca spp.) but causes subclinical infections in patas monkeys (Cercopithecinae: Erythrocebus patas). This difference in disease course offers a unique opportunity to compare host responses to infection by a VHF-causing virus in biologically similar susceptible and refractory animals. Patas and rhesus monkeys were inoculated side-by-side with SHFV. Unlike the severe disease observed in rhesus monkeys, patas monkeys developed a limited clinical disease characterized by changes in complete blood counts, serum chemistries, and development of lymphadenopathy. Viral RNA was measurable in circulating blood 2 days after exposure, and its duration varied by species. Infectious virus was detected in terminal tissues of both patas and rhesus monkeys. Varying degrees of overlap in changes in serum concentrations of interferon (IFN)-γ, monocyte chemoattractant protein (MCP)-1, and interleukin (IL)-6 were observed between patas and rhesus monkeys, suggesting the presence of common and species-specific cytokine responses to infection. Similarly, quantitative immunohistochemistry of livers from terminal monkeys and whole blood flow cytometry revealed varying degrees of overlap in changes in macrophages, natural killer cells, and T-cells. The unexpected degree of overlap in host response suggests that relatively small subsets of a host’s response to infection may be responsible for driving hemorrhagic fever pathogenesis. Furthermore, comparative SHFV infection in patas and rhesus monkeys offers an experimental model to characterize host–response mechanisms associated with viral hemorrhagic fever and evaluate pan-viral hemorrhagic fever countermeasures.

Sign in / Sign up

Export Citation Format

Share Document