Posts Tagged ‘infection’

What exactly happens when a virus infects a host?

Monday, July 9th, 2012

Stress granules There have been some great papers published recently summarizing the interactions which take place between virus and host during infection.

The first to grab my eye was: Inflammasomes and viruses: cellular defence versus viral offence. J Gen Virol. 27 Jun 2012. This paper reviews multimeric complexes known as “inflammasomes”, a key feature in the activation of the the innate arm of the host immune system.

Zooming into the depths of the cell brings us to How Do Viruses Interact with Stress-Associated RNA Granules? (2012) PLoS Pathog 8(6): e1002741. Host mRNAs are always dynamically exchanged between translating and non-translating pools. Non-translating pools are organized into specialized RNA granules called stress granules (SGs) and processing bodies (PBs), which have fundamental roles in inhibition and degradation of host mRNAs. Virus infection usually results in interference in many cell processes in ways that directly induce stress responses. Cells respond to many types of stress by transient global inhibition of protein synthesis in order to promote cell survival through restricted consumption of nutrients and energy. This can also redirect gene expression and resources to damage repair pathways.


Great stuff, really getting to the heart of what goes on in the battle between virus and host.

The Virological Synapse

Friday, February 12th, 2010

Synapse As obligate intracellular parasites, viruses have evolved diverse mechanisms to enter and exit from host cells. A requirement that is shared by all animal viruses is the use of cellular receptors for entry into cells to initiate viral infection. Receptors can function in virus attachment to the cell surface and can also mediate virus internalization and penetration of the cell membrane. Receptors are often grouped into “primary receptors” and “secondary receptors” or “co-receptors” depending either on their function in the virus entry process or historical precedence.

Viruses can be classified into two broad groups: enveloped and non-enveloped. Direct cell-to-cell spread has only been described for enveloped viruses. Viruses that spread directly from infected to uninfected cells can avoid the obstacles to infection which occur for for infection via free virus particles (biophysical and immunological). Once the initial infection has occurred, the cell-to-cell mode of virus spread enables direct infection of target cells by adjacent infected cells – a very efficient process.

Direct cell-to-cell spread requires intimate contact between cells and can occur at tight junctions between cells or neurological synapses. Immune cells contain machinery that allows them to polarize their secretory apparatus towards a second cell that is involved in an immunological synapse. This machinery can be subverted by retroviruses such as HTLV-1 and HIV-1 to form a virological synapse. Virions bud from the infected cell into the synapse, from where they fuse with the target-cell plasma membrane. Certain viruses have therefore engineered novel structures in infected cells to promote more efficient spread within the host.

Avoiding the void: cell-to-cell spread of human viruses. 2008 Nature Reviews Microbiology 6: 815-826. doi:10.1038/nrmicro1972
The initial stages of animal virus infection are generally described as the binding of free virions to permissive target cells followed by entry and replication. Although this route of infection is undoubtedly important, many viruses that are pathogenic for humans, including HIV-1, herpes simplex virus and measles, can also move between cells without diffusing through the extracellular environment. Cell-to-cell spread not only facilitates rapid viral dissemination, but may also promote immune evasion and influence disease. This review discusses the various mechanisms by which viruses move directly between cells and the implications of this for viral dissemination and pathogenesis.


Rethinking dengue hemorrhagic fever

Wednesday, October 28th, 2009

Dengue virus Dengue virus infection usually causes a severe flu like illness, although symptoms may be mild in young children. DHF, however, is a severe and sometimes fatal complication of dengue virus infection that affects about half a million people every year after infection with any one of the four dengue virus (DENV) serotypes. DHF patients usually fall into two groups; children and adults who become infected with a second dengue virus serotype after an initial primary dengue virus infection with a different serotype, and infants with primary dengue virus infections born to mothers who have some dengue virus immunity. The widely accepted explanation for the pathogenesis of DHF in these settings, particularly during infancy, is antibody-dependent enhancement (ADE) of DENV infection.

Researchers conducted a prospective nested case-control study of DENV infections during infancy. Clinical data and blood samples were collected from 4,441 mothers and infants in up to two pre-illness study visits, and surveillance was performed for symptomatic and inapparent DENV infections. Pre-illness plasma samples were used to measure the associations between maternally derived anti-DENV3 antibody-neutralizing and enhancing capacities at the time of DENV3 infection and development of infant DHF. The study examined 60 infants with DENV infections across a wide spectrum of disease severity. DENV3 was the predominant serotype among the infants with symptomatic (35/40) and inapparent (15/20) DENV infections, and 59/60 infants had a primary DENV infection. The estimated in vitro anti-DENV3 neutralizing capacity at birth positively correlated with the age of symptomatic primary DENV3 illness in infants. At the time of symptomatic DENV3 infection, essentially all infants had low anti-DENV3 neutralizing activity and measurable DENV3 ADE activity. The infants who developed DHF did not have significantly higher frequencies or levels of DENV3 ADE activity compared to symptomatic infants without DHF. A higher weight-for-age in the first 3 mo of life and at illness presentation was associated with a greater risk for DHF from a primary DENV infection during infancy. This prospective nested case-control study of primarily DENV3 infections during infancy has shown that infants exhibit a full range of disease severity after primary DENV infections.

The current model for development of DHF in infants around 6 months old is that anti-dengue virus antibodies transferred from a dengue-immune mother to her child somehow enhance dengue virus infection, resulting in more severe symptoms (the  antibody-dependent enhancement  model). These results support an initial in vivo protective role for maternally derived antibody. There was no significant association between DENV3 ADE activity at illness onset and the development of DHF compared with less severe symptomatic illness. The results of this study should encourage rethinking or refinement of the current ADE pathogenesis model for infant DHF and stimulate new directions of research into mechanisms responsible for the development of DHF during infancy.

A Prospective Nested Case-Control Study of Dengue in Infants: Rethinking and Refining the Antibody-Dependent Enhancement Dengue Hemorrhagic Fever Model. PLoS Med 6(10): e1000171 doi:10.1371/journal.pmed.1000171


Bacterial immune evasion

Monday, October 26th, 2009

Staphylococcus aureus In mammals, adenosine assumes an essential role in regulating innate and acquired immune responses. Strong or excessive host inflammatory responses, e.g. in response to bacterial infection, exacerbate the tissue damage inflicted by invading pathogens. Successful immune clearance of microbes therefore involves the balancing of pro- and anti-inflammatory mediators. The cytokines IL-4, IL-10, IL-13, and TGF-β play a role in restricting excessive inflammation, but only adenosine is able to completely suppress immune responses. The immunoregulatory attributes of adenosine are mediated via four transmembrane adenosine receptors: A1, A2A, A2B, and A3. T lymphocytes express the high affinity A2A receptor as well as the low affinity A2B receptor. Depending on their activation state, macrophages and neutrophils express all four adenosine receptors, whereas B cells harbor only A2A. Engagement of A2A inhibits IL-12 production, increases IL-10 in monocytes and dendritic cells, and decreases cytotoxic attributes and chemokine production in neutrophils. Generation of adenosine at sites of inflammation, hypoxia, organ injury, and traumatic shock is mediated by two sequential enzymes.

Although extracellular adenosine is essential for the suppression of inflammation, build-up of excess adenosine is also detrimental. This is exemplified in patients with a deficiency in adenosine deaminase, an enzyme that converts adenosine to inosine. Adenosine deaminase deficiency causes severe compromised immunodeficiency syndrome, with impaired cellular immunity and severely decreased production of immunoglobulins. As the regulation of extracellular adenosine is critical in maintaining immune homeostasis, perturbation of adenosine levels is likely to affect host immune responses during infection.

Staphylococcus aureus infects hospitalized or healthy individuals and represents the most frequent cause of bacteremia, treatment of which is complicated by the emergence of methicillin-resistant S. aureus. Scientists examined the ability of S. aureus to escape phagocytic clearance in blood and identified adenosine synthase A (AdsA), a cell wall–anchored enzyme that converts adenosine monophosphate to adenosine, as a critical virulence factor. Staphylococcal synthesis of adenosine in blood, escape from phagocytic clearance, and subsequent formation of organ abscesses were all dependent on adsA and could be rescued by an exogenous supply of adenosine. An AdsA homologue was identified in the anthrax pathogen Bacillus anthracis, and adenosine synthesis also enabled escape of B. anthracis from phagocytic clearance. Collectively, these results suggest that staphylococci and other bacterial pathogens exploit the immunomodulatory attributes of adenosine to escape host immune responses.

Staphylococcus aureus synthesizes adenosine to escape host immune responses. J. Exp. Med. 28 Sep 2009 doi:10.1084/jem.20090097

Staphylococcus aureus: superbug
Evolution and pathogenesis of Staphylococcus aureus

How human pathogenic fungi sense and adapt to pH

Friday, September 11th, 2009

Candida albicans The ability of fungal pathogens to cause disease is dependent on the ability to grow within the human host environment. In general, the human host environment can be considered a slightly alkaline environment, and the ability of fungi to grow at this pH is essential for pathogenesis. The Rim101 signal transduction pathway is the primary pH sensing pathway described in the pathogenic fungi, and in Candida albicans, it is required for a variety of diseases. As more detailed analyses have been conducted studying pathogenesis at the molecular level, it has become clear that the Rim101 pathway, and pH responses in general, play an intimate role in pathogenesis beyond simply allowing the organism to grow.

The mammalian host environment can generally be considered to be at a pH slightly greater than neutral. The pH of human blood and tissues is 7.4 ± 0.1; the pH of murine blood and tissues is 7.2 ± 0.1. However, this represents a rather limited view of the host environment from a standpoint of pH, when mucosal and other sites exposed to the outside world are considered, dramatic variations from this slightly alkaline pH are found. One obvious example is the digestive track, which shows spatial variations in pH from extremely acidic (pH < 2.0) to more alkaline (pH > 8.0). Further, temporal changes in pH within a single site have been well documented, such as within the oral cavity following the fermentation of dietary sugar by endogenous microbes. The vaginal cavity is an acidic environment, pH 4; however, increases in vaginal pH occur in conjunction with menses. Thus, while fungi must be able to adapt to changes in pH within the host, most if not all pathogenic fungi must be able to thrive at neutral-alkaline pH within host tissues in order to cause disease. This paper discusses the signaling pathways required for growth and adaptation to host pH and the contributions these pathways make to pathogenesis.

Recent studies have found that the pathways responsible for sensing and responding to environmental pH have been co-opted for adaptation to the mammalian host. The pathogenic fungi, including C. albicans, C. neoformans, and A. nidulans, face physical and chemical stresses due to neutral-alkaline pH similarly to environmental fungi, such as S. cerevisiae, such as iron starvation. What has been somewhat surprising is that these pH sensing pathways also control expression of virulence traits not necessarily predicted to be associated with pH, including adhesion to host cells, tissue invasion, as well as other virulence attributes. This highlights the importance of continuing studies of these fundamental pH response pathways in pathogenic fungi in order to understand how these pathogens are adapted to the mammalian host and potentially identify new approaches for preventing or treating infections.

How human pathogenic fungi sense and adapt to pH: the link to virulence. Curr Opin Microbiol. 23 July 2009. doi:10.1016/j.mib.2009.05.006


The search for infectious causes of human cancers

Wednesday, September 9th, 2009

Infectious causes of human cancers Slightly more than 20% of the global cancer burden can presently be linked to infectious agents, including viruses, bacteria and parasites. This manuscript analyzes reasons for their relatively late discovery and highlights epidemiological observations that may point to an involvement of additional infectious agents in specific human cancers. A number of infectious agents have been identified which either cause or contribute to specific human cancers. They include two members of the herpes virus family, Epstein–Barr virus and human herpesvirus type 8, high risk and low risk human papillomaviruses (HPV), Hepatitis B and C viruses, a recently identified human polyomavirus, Merkel cell polyomavirus, the human T-lymphotropic retrovirus type 1 (HTLV-1), and human immunodeficiency viruses (HIV) types 1 and 2. In addition, human endogenous retroviruses have been suspected to play a role in human cancers. Besides viruses, other pathogens have also been identified. They include the bacterium Helicobacter pylori, a major contributor to gastric cancer, and parasitic infections, here in particular Schistosoma hematobium, a major cause of bladder cancer in Egypt, and liver flukes.

Although we know that presently slightly more than 20% of the global cancer incidence is linked to infectious events, some epidemiological observations suggest that this percentage will increase in the future. The recognition that no cancer linked to infections develops without additional modifications within the host cell genome permits the speculation that even cancers with well established chromosomal modifications deserve a careful analysis for an additional involvement of infectious agents. Prime malignancies suggested here as candidates for potential links with infections are hematopoietic malignancies, particularly childhood lymphoblastic leukemias, Epstein–Barr virus-negative Hodgkin’s lymphomas, basal cell carcinomas of the skin, and breast, colorectal and a subgroup of lung cancers. Although still hypothetical, this proposal is accessible to experimental verification. Even if only one of these speculations turns out to be correct, this would have profound implications for the prevention, diagnosis and hopefully also for therapy of the respective malignancy.

The search for infectious causes of human cancers: where and why. 2009 Virology 392(1): 1-10


An introduction to T cells

Friday, August 21st, 2009

Nice introduction on YouTube:


Herpes Gladiatorum: a combative virus

Tuesday, August 11th, 2009

Herpes simplex Players of contact sports like rugby and wrestling can end up with an infection caused by Herpes Gladiatorum (HG), a virus belonging to the herpes family. It gets into the body through cuts and abrasions and the disease is sometimes called scrumpox. Like all herpes viruses, once contracted, HG can remain dormant in its host and reactivate at any time. In this article in Microbiology Today (pdf) Julia Colston and Judy Breuer take a look at this unpleasant disease and show how it can even wreck an athletic career:

Herpes Gladiatorum (HG) is an active herpes simplex virus (HSV) infection associated with close-contact traumatic sports, such as wrestling, rugby and martial arts. Other names for the condition include scrumpox in association with rugby, and matpox in wrestling. It was first described in the literature in 1964, where five members of a small amateur wrestling group (and a further unfortunate gymnast who had volunteered themselves for a demonstration of the crossface manoeuvre!) developed lesions within a close time frame of individual fighting episodes. All five of these cases could be linked and they presented with similar symptoms of general malaise and an atypical vesicular rash affecting the exposed areas, namely the face and arms. Several further reports closely followed in 1965. It seems that outbreaks of HG were occurring well before this, with many unpublished epidemics taking place amongst wrestling groups. HG might have been described much earlier, had it not been for the ambiguity of the lesions produced, superimposed infections and a lack of appreciation for the relevance of the disease. Early reports list a vast array of alternative diagnoses, such as staphylococcal infections, herpes zoster, rickettsialpox and contact dermatitis, to name just a few. In fact, there are reports of unspecified disease in wrestling groups dating back as far as the 1920’s.

Read more


The Anatomy of Virus Persistence

Monday, August 10th, 2009

LCMV The many millions of humans who have life-long virus infections represent a major health issue for the 21st century but also a unique opportunity for investigative virologists. For persistent virus infections to endure, two ingredients are essential. The first is a unique strategy of viral replication; that is, instead of killing its host cell, the pathogen causes little to no damage so it can continue to reside in those cells. The second requirement for persistent virus infection is an immune response that does not react to or remove virus-infected cells. Overall, our knowledge of how viral genes and cellular factors interact to allow persistence to occur is incomplete. Although our libraries contain volumes of facts on this subject, many physiologic functions and interrelationships of viral genes with host genes that establish persistence remain, in large part, unknown.

We do know that acutely infected cells express viral peptides, which, when attached to host major histocompatibility complex (MHC) molecules on their surfaces, signal the immune system to kill such cells. However, viruses apply numerous avoidance strategies to persist. One is direct selective pressure to suppress the infected host’s innate and/or adoptive immune system that would otherwise destroy them. For example, viruses can alter or interfere with the processing of viral peptides by professional antigen-presenting cells, thereby restricting expression of MHC/peptide complexes on cell surfaces, a requirement for activation and expansion of the T cells that normally remove infected cells. Additionally, viruses can downregulate co-stimulatory and/or MHC molecules also required for T cell signaling and expansion; they can inhibit the differentiation of antigen-presenting conventional dendritic cells (cDCs), and can infect effector T and B cells directly. Similarly, to persist in infected cells, viruses can disrupt the processing or migration of viral peptides or viral peptide/MHC complexes to the cells’ surface, thereby removing the recognition signals for activated killer T cells. Finally, viruses that persist frequently infect neurons, which have defects in TAP, a molecule required for the translocation of viral peptides to endoplasmic reticulum (ER). Perhaps neurons can also actively prevent cytotoxic T lymphocytes (CTLs) or natural killer (NK) cells from degranulating and thereby limit the activity of such virus-removing effector cells. Since neurons are essential to health but rarely regenerate when destroyed, Darwinian selection likely caused them to evolve mechanisms to avoid immunologic assault. Such events would allow infected neurons to escape immune recognition and live, as well as allow viruses to persist in a neuronal safe house.

Currently researchers are engaged in the discovery of additional negative immune regulators and their signaling pathway(s) using gene chip and forward genetics technology. These projects have a multitude of applications. Some examples are the development of pharmacologic small molecules as effective antagonists of negative immune regulators, the use of transient negative regulator blockers as an adjuvant approach to enhance both prophylactic and therapeutic vaccination, and the determination of how long during the course of persistent virus infection exhausted T cells can be rescued to become antiviral effector T cells. As always, the goal is to understand basic principles in viral pathogenesis and to extend results in the murine model to resolve persistent infections of humans.

Anatomy of Viral Persistence. PLoS Pathog 5(7): e1000523 doi:10.1371/journal.ppat.1000523