Posts Tagged ‘Immunology’

HSV-1 evasion of the host humoral immune system

Thursday, March 13th, 2014

HSV-1 evasion of the host humoral immune system I’ve been banging on to my final year students about how clever heresviruses are at evading the immune response. No sooner do I close my mouth than another one comes along:

Herpes Simplex Virus 1 (HSV-1) infects 40–80% of adults worldwide. HSV-1 initiates infection at mucosal surfaces and spreads along sensory neurons to establish a life-long latent infection that can lead to neurological diseases. Humans usually develop IgG antibodies that specifically recognize pathogens via fragment antigen binding (Fab) variable regions. HSV-1 can avoid the protective effects of antibodies by producing gE-gI, a receptor that binds to the constant portion of IgGs (Fc), tethering the antibody in a position where it cannot trigger downstream immune functions. A gE-gI–bound IgG can participate in antibody bipolar bridging (ABB) such that the Fabs bind a viral antigen and the Fc binds gE-gI. The fate of ABB complexes had been unknown. This paper uses used live cell fluorescent imaging to follow ABB complexes during their formation and transport within a cell. ABB assemblies were internalized into acidic intracellular compartments, where gE-gI dissociated from IgG–viral antigen complexes and the IgG and antigen were targeted for degradation within lysosomes. These results suggest that gE-gI mediates clearance of infected cell surfaces of both anti-viral IgGs and viral antigens, a general mechanism to facilitate latent infection by evading IgG-mediated responses.

The Herpes Virus Fc Receptor gE-gI Mediates Antibody Bipolar Bridging to Clear Viral Antigens from the Cell Surface. (2014) PLoS Pathog 10(3): e1003961. doi:10.1371/journal.ppat.1003961

Why Bees Need Their AMPs

Tuesday, October 1st, 2013

Bee Bumblebees, amongst the most important of pollinators, are under enormous population pressures. One of these is disease. The bumblebee and its gut trypanosome Crithidia bombi are one of the fundamental models of ecological immunology. Although there is previous evidence of increased immune gene expression upon Crithidia infection, recent work has focussed on the bumblebee’s gut microbiota. By knocking down gene expression using RNAi, Leicester research shows for the first time that antimicrobial peptides (AMPs) have a functional role in anti-Crithidia defense.

 

Antimicrobial peptides play a functional role in bumblebee anti-trypanosome defense. (2013) Dev Comp Immunol. doi: 10.1016/j.dci.2013.09.004

 

How, exactly, do prion proteins cause disease?

Monday, August 5th, 2013

Prion Protein Fibrils via NIAID When prions were first discovered in the 1980s it was immensely controversial whether an isolated protein molecule could act as an infectious agent without any associated nucleic acid, that is, without a genome to encode future generations. I was lucky enough to be able to follow from the sidelines as the prion story slowly unfolded throughout the 1990s. By and large, most of the major questions about prions seem now to have been answered, but one big issue still remains – how exactly do these proteins cause disease?

In contrast to the normally-folded cellular form of the prion protein found in “uninfected” cells, the misfolded disease-causing version of the protein is toxic to brain cells. In a new paper in Nature, Adriano Aguzzi’s group suggests that the prion protein contains a “switch” that controls its toxicity. This switch covers a tiny area on the surface of the protein. If another molecule, for example an antibody, touches this switch, a lethal mechanism is triggered that can lead to very fast cell death (The flexible tail of the prion protein mediates the toxicity of antiprion antibodies. Nature, 31 July 2013 doi: 10.1038/nature12402 - sorry, subscription).

The prion protein consists of two functionally distinct parts: a globular domain, which is tethered to the cell membrane, and a long and unstructured tail. Under normal conditions, the tail is important in order to maintain the functioning of nerve cells. In contrast, in the case of prion infections the pathogenic prion protein interacts with the globular part and the tail causes cell death.

Proteins with similarities to prions also play a role in the pathogenesis of other diseases, such as Creutzfeldt-Jakob disease and possibly some forms of Alzheimer’s, Parkinson’s, Huntington’s, and Lou Gehrig’s disease. Aguzzi et al suggest that prion tail-mediated toxicity could conceivably play a role in these conditions, and that it may be worthwhile screening patients with idiopathic neurodegeneration for disease-causing autoantibodies.

Currently there is no epidemiological evidence for the spreading and/or acceleration of other protein misfolding diseases due to the transfer of misfolded proteins via natural or iatrogenic routes – that is, no evidence that Alzheimer’s, Parkinson’s or Huntington’s disease are infectious in the same way that CJD and other transmissible spongiform encephalopathies (TSEs) are. Such epidemiological evidence may be difficult to interpret for many of these diseases given their multifactorial etiologies and typically long preclinical and clinical phases. However, given the high incidence of diseases such as Alzheimer’s, Parkinson’s, Huntington’s, and Lou Gehrig’s (ALS), it is important to know whether even a small percentage of cases can be initiated by transmission events. Even in the absence of significant human-to-human transmission routes, it is critical to establish whether prion-like propagation of protein misfolding within individuals can be observed and manipulated to alter the course of disease.

Know what triggers prion proteins to cause trouble also provides a possible route of preventing or at least slowing down such diseases. You can bet that a lot of investigators will be looking for triggering antiboes in a wide range of such diseases over the next few years. And if they find them, we can start working on ways to defeat these conditions.

 

Prions and the Potential Transmissibility of Protein Misfolding Diseases. (2013) Annual Review of Microbiology, 67 doi: 10.1146/annurev-micro-092412-155735
Prions, or infectious proteins, represent a major frontier in the study of infectious agents. The prions responsible for mammalian transmissible spongiform encephalopathies (TSEs) are due primarily to infectious self-propagation of misfolded prion proteins. TSE prion structures remain ill-defined, other than being highly structured, self-propagating, and often fibrillar protein multimers with the capacity to seed, or template, the conversion of their normal monomeric precursors into a pathogenic form. Purified TSE prions usually take the form of amyloid fibrils, which are self-seeding ultrastructures common to many serious protein misfolding diseases such as Alzheimer’s, Parkinson’s, Huntington’s and Lou Gehrig’s (amytrophic lateral sclerosis). Indeed, recent reports have now provided evidence of prion-like propagation of several misfolded proteins from cell to cell, if not from tissue to tissue or individual to individual. These findings raise concerns that various protein misfolding diseases might have spreading, prion-like etiologies that contribute to pathogenesis or prevalence.

 

Reovirus Activates a Caspase-Independent Cell Death Pathway

Friday, May 24th, 2013

Necroptosis Virus-induced cell death is a determinant of pathogenesis. Mammalian reovirus is a versatile experimental model for identifying viral and host intermediaries that contribute to cell death and for examining how these factors influence viral disease. In this study, we identified that in addition to apoptosis, a regulated form of cell death, reovirus is capable of inducing an alternate form of controlled cell death known as necroptosis. Death by this pathway perturbs the integrity of host membranes and likely triggers inflammation. We also found that apoptosis and necroptosis following viral infection are activated by distinct mechanisms. Results suggest that host cells can detect different stages of viral infection and attempt to limit viral replication through different forms of cellular suicide. While these death responses may aid in curbing viral spread, they can also exacerbate tissue injury and disease following infection.

 

Reovirus activates a caspase-independent cell death pathway. MBio. 2013 May 14; 4(3). pii: e00178-13. doi: 10.1128/mBio.00178-13
Virus-induced apoptosis is thought to be the primary mechanism of cell death following reovirus infection. Induction of cell death following reovirus infection is initiated by the incoming viral capsid proteins during cell entry and occurs via NF-κB-dependent activation of classical apoptotic pathways. Prototype reovirus strain T3D displays a higher cell-killing potential than strain T1L. To investigate how signaling pathways initiated by T3D and T1L differ, we methodically analyzed cell death pathways activated by these two viruses in L929 cells. We found that T3D activates NF-κB, initiator caspases, and effector caspases to a significantly greater extent than T1L. Surprisingly, blockade of NF-κB or caspases did not affect T3D-induced cell death. Cell death following T3D infection resulted in a reduction in cellular ATP levels and was sensitive to inhibition of the kinase activity of receptor interacting protein 1 (RIP1). Furthermore, membranes of T3D-infected cells were compromised. Based on the dispensability of caspases, a requirement for RIP1 kinase function, and the physiological status of infected cells, we conclude that reovirus can also induce an alternate, necrotic form of cell death described as necroptosis. We also found that induction of necroptosis requires synthesis of viral RNA or proteins, a step distinct from that necessary for the induction of apoptosis. Thus, our studies reveal that two different events in the reovirus replication cycle can injure host cells by distinct mechanisms.

 

Sometimes it pays to be recognized

Tuesday, April 16th, 2013

Model HIV may not always want to go unnoticed. It is known that HIV replicates more efficiently in TH cells that have been activated, and this presents the virus with a bit of a dilemma – it certainly doesn’t pay to be recognized by CTLs, the hired assassins of the immune system. But there’s also a possible benefit in triggering the activation of the TH cells that they’ve infected. Where does the balance lie? Is it conceivable that there are some conditions where it is better for HIV epitopes to be recognized than to be ignored?

To answer this question, scientists have built a complex mathematical model of interactions between TH cells, CTLs, antigen-presenting cells and viruses. They set up two different versions of the model – one with a virus that infects non-immune cells (like HCV infecting hepatocytes), and one with a virus that infects T cells (like HIV). The results are quite striking – in the case of HCV, evasion always pays off. But in the case of HIV, the dependence on TH activation seems to sometimes favor virus epitopes that are strongly recognized by cellular immune system. The authors propose that recognition of HIV epitopes by TH cells can be beneficial for the long-term survival of the virus within the body. Another key variable is how many TH cells are activated in the body by pathogens other than HIV. If this “background activation” is strong, HIV obtains no payoffs from being recognized. Studying the sequence data confirms that in the capsid genes (Gag) it is TH epitopes, rather than CTL epitopes, that are constrained and that epitopes stay the same within patient viral populations rather than between patients, again implicating chronic internal transmission between cells.

There is an important practical implication of these findings. If this model is correct, then HIV vaccines based on TH epitopes might prove counterproductive, playing into the hands of the virus. Instead, vaccines should target only CTL-specific viral epitopes.

 

HIV Plays (and Wins) a Game of T Cell Brinkmanship. (2013) PLoS Biol 11(4): e1001521. doi:10.1371/journal.pbio.1001521

Fifty Shades of Immune Defence

Wednesday, April 3rd, 2013

Fifty Shades of Immune Defense

This great paper appeared in PLOS Pathogens recently. I’ll let you read it for yourself, but to summarize:

In their struggle to survive and thrive, all living things must defend themselves from predatory attack. Microbes, in the form of parasites, bacteria, fungi, and viruses, are life’s most accomplished predators. Therefore, all living things have evolved mechanisms to defend against them. Historically, biological defense systems have been classified into two broad categories – innate systems that provide nonspecific defense against invading pathogens and adaptive systems that provide long-lasting defense against attack by specific pathogens. Recently, a growing body of literature in comparative immunology has indicated that these categories may not be as distinct as was originally believed. Instead, a variety of immune mechanisms that share properties of both innate and adaptive systems have been recently elucidated. This papers describes five key facts about the newly appreciated shades of grey between innate and adaptive defense systems:

  1. Innate and Adaptive Immunity Are No Longer Black and White; There Are Increasing Shades of Grey
  2. The Immunoglobulin Superfamily (IgSF) Is Neither the Only Nor the Oldest Antigen Receptor System
  3. Invertebrate Immune Cells Have Complex Receptor Systems, Possibly Affording Adaptive Immunity
  4. Forms of Immunological Memory May Well Exist in Nonvertebrates, Even in Prokaryotes
  5. Comparative Immunologists Will Not Be the Sole Beneficiaries of These Discoveries

Fifty Shades of Immune Defense. (2013) PLoS Pathog 9(2): e1003110. doi:10.1371/journal.ppat.1003110

Rotavirus Roundup

Monday, March 18th, 2013

Rotaviruses There have been several interesting papers recently on responses to rotavirus infection, so I thought I’d round them up in one place:

 

The Battle between Rotavirus and Its Host for Control of the Interferon Signaling Pathway. (2013) PLoS Pathog 9(1): e1003064
Viral pathogens must overcome innate antiviral responses to replicate successfully in the host organism. Some of the mechanisms viruses use to interfere with antiviral responses in the infected cell include preventing detection of viral components, perturbing the function of transcription factors that initiate antiviral responses, and inhibiting downstream signal transduction. RNA viruses with small genomes and limited coding space often express multifunctional proteins that modulate several aspects of the normal host response to infection. One such virus, rotavirus, is an important pediatric pathogen that causes severe gastroenteritis, leading to ~450,000 deaths globally each year. This review discusses the nature of the innate antiviral responses triggered by rotavirus infection and the viral mechanisms for inhibiting these responses.

 

The impact of Rotavirus mass vaccination on hospitalization rates, nosocomial Rotavirus gastroenteritis and secondary blood stream infections. (2013) BMC Infect Dis. 13(1): 112
The aim of this study was to evaluate the effects of universal mass vaccination (UMV) against rotavirus (RV) on the hospitalization rates, nosocomial RV infections and RV-gastroenteritis (GE)-associated secondary blood stream infections (BSI).
Retrospective evaluation (2002-2009) by chart analysis included all clinically diagnosed and microbiologically confirmed RV-GE cases in a large tertiary care hospital in Austria. The pre-vaccination period (2002-2005) was compared with the recommended and early funded (2006–2007) and the funded (2008–2009) vaccination periods. Primary outcomes were RV-GE-associated hospitalizations, secondary outcomes nosocomial RV disease, secondary BSI and direct hospitalization costs for children and their accompanying persons.
In 1,532 children with RV-GE, a significant reduction by 73.9% of hospitalized RV-GE cases per year could be observed between the pre-vaccination and the funded vaccination period, which was most pronounced in the age groups 0-11 months (by 87.8%), 6-10 years (by 84.2%) and 11-18 years (88.9%). In the funded vaccination period, a reduction by 71.9% of nosocomial RV-GE cases per year was found compared to the pre-vaccination period. Fatalities due to nosocomial RV-GE were only observed in the pre-vaccination period (3 cases). Direct costs of hospitalized, community-acquired RV-GE cases per year were reduced by 72.7% in the funded vaccination period. The reduction of direct costs for patients (by 86.9%) and accompanying persons (86.2%) was most pronounced in the age group 0-11 months.
UMV may have contributed to the significant decrease of RV-GE-associated hospitalizations, to a reduction in nosocomial RV infections and RV-associated morbidity due to secondary BSI and reduced direct hospitalization costs. The reduction in nosocomial cases is an important aspect considering severe disease courses in hospitalized patients with co-morbidities and death due to nosocomial RV-GE.

 

Innate cellular responses to rotavirus infection. J Gen Virol. 13 Mar 2013
Rotavirus is a leading cause of severe dehydrating diarrhoea in infants and young children. Following rotavirus infection in the intestine an innate immune response is rapidly triggered. This response leads to the induction of type I and type III interferons (IFNs) and other cytokines, resulting in a reduction in viral replication. Here we review the current literature describing the detection of rotavirus infection by pattern recognition receptors within host cells, the subsequent molecular mechanisms leading to IFN and cytokine production, and the processes leading to reduced rotavirus replication and the development of protective immunity. Rotavirus countermeasures against innate responses, and their roles in modulating rotavirus replication in mice, also are discussed. By linking these different aspects of innate immunity we provide a comprehensive overview of the host’s first line of defence against rotavirus infection. Understanding these processes is expected to be of benefit in improving strategies to combat rotavirus disease.

 

It’s not all down to the virus

Monday, February 4th, 2013

DNA When we think about virus pathogensis, we tend to get hung up on genetic variation and new “virulent” strains of virus appearing. The recent example of the Sydney 2012 strain of norovirus is a good example of this.

But we also know that around 20% of Europeans are highly resistant to symptomatic infections by noroviruses (Mendelian resistance to human norovirus infections. (2006) Seminars in immunology 18(6): 375-386).

Likewise, host variation in the IL28B gene is responsible for the outcome of hepatitis C virus (HCV) infection (Genetic Variation in the Interleukin-28B Gene Is Associated with Spontaneous Clearance and Progression of Hepatitis C Virus in Moroccan Patients. (2013) PLoS ONE 8(1): e54793).

So when you get sick, make sure you take your fair share of the responsibility!

 

A novel role for lipid droplets in the antibacterial response

Wednesday, January 16th, 2013

Drosophila embryos Histones are proteins found in large numbers in most animal cells, where their primary job is to help DNA strands fold into compact and robust structures inside the nucleus. In vitro, histones are very effective at killing bacteria, and there is some evidence that histones secreted from cells provide protection against bacteria living outside cells. However, many types of bacteria are able to enter cells, where they can avoid the immune system and go on to replicate.

Researchers have discovered that histones can bind to lipid droplets – organelles in the cytosol that are primarily used to store energy – in various animal cells and tissues. Histones bound to lipid droplets can protect cells against bacteria without causing the harm normally associated with the presence of free histones.

 

A novel role for lipid droplets in the organismal antibacterial response. (2013) eLife doi: 10.7554/eLife.00003
We previously discovered histones bound to cytosolic lipid droplets (LDs); here we show that this forms a cellular antibacterial defense system. Sequestered on droplets under normal conditions, in the presence of bacterial lipopolysaccharide (LPS) or lipoteichoic acid (LTA), histones are released from the droplets and kill bacteria efficiently in vitro. Droplet-bound histones also function in vivo: when injected into Drosophila embryos lacking droplet-bound histones, bacteria grow rapidly. In contrast, bacteria injected into embryos with droplet-bound histones die. Embryos with droplet-bound histones displayed more than a fourfold survival advantage when challenged with four different bacterial species. Our data suggests that this intracellular antibacterial defense system may function in adult flies, and also potentially in mice.