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Immunology Update - September 2017

Welcome to the next installment of our regular update where we report on research from the world of immunology, highlighting work from BSI members that has hit the headlines over the past few weeks.


B cell DNA damage response ready to spring into action with the help of Tia1

B cells live precarious lives. Programmed DNA damage is vital at several different stages of B cells’ development and activation, enabling the creation of the enormous repertoire of highly diverse antibodies. However, there is a fine line between the DNA damage that forms an essential part of B cells’ life and DNA damage that could end it. Consequently, the process of DNA damage repair is tightly controlled.

Research conducted at the Babraham Institute by a team including BSI members, Manual Diaz-Muñoz and Martin Turner, and reported in Nature Communications, has recently identified a protein called Tia1 as important in this process.  This RNA binding protein, upregulated upon B cell activation, post-transcriptionally regulates components of the DNA damage repair machinery, such as p53, silencing the mRNA and keeping the transcripts captive in RNA stress granules. Upon DNA damage, ATM induces Ria1 to release its constraints on p53 mRNA, enabling the translocation and translation of the DNA damage response protein transcript. 

Through regulating protein abundance via post-transcriptional methods, Tia1 permits the DNA damage response to spring into action rapidly when DNA damage becomes a dangerous threat.

Dr Martin Turner said: “Remarkably, our data suggest that regulation of mRNAs by Tia1 rather than protein destruction controls DNA repair in activated B cells. This is an attractive and little explored mechanism that we are now starting to understand. Controlling protein production in this way is important in other healthy and diseased cells and it will be interesting to see if a similar system exists in other places.”

 

Read the full press release here.

Read the full paper here: Diaz-Muñoz et al. 2017 Nature Communications DOI: 10.1038/s41467-017-00454-2

 


Potential new therapies to put a stop to hijacking pathogens

Phagocytes are crucial members of our immune system, patrolling for foreign pathogens and subsequently engulfing and destroying them. However, some pathogens have evolved mechanisms to evade such clearance. Instead they manage to survive and thrive inside, and in some cases, utilise the immune cell as a means of transport around the body.

Vomocytosis is a process adopted by phagocytes to eject the pathogens they can no longer destroy. Although evolutionarily conserved, the underlying mechanism has, until recently, remained unknown. New research, led by the University of Birmingham and published in Science Advances, has uncovered the atypical MAP kinase ERK5 as an important suppressor of vomocytosis. Through first pharmacological and later genetic means, the group demonstrate that inhibition of ERK5 causes an enhancement of vomocytosis. Furthermore, stimulation of ERK5 via the MEK5–ERK5 signaling axis was shown to suppress expulsion. In a zebrafish model of cryptococcal disease, a decrease in ERK5 activity led to reduced dissemination of infection by an increase in vomocytosis. This opens up the question of potential ‘vomocytosis-modulating therapies’, especially as there are numerous ‘ERK5 inhibitors under clinical development’.

BSI member Professor Robin May, Director of the Institute of Microbiology & Infection at the University of Birmingham, said: “If we can develop ways to manipulate this [vomocytosis] and encourage the white blood cells to recognise and expel organisms like this, we might be able to limit the spread of infection not only for Cryptococcosis but for other invasive pathogens that are a significant threat to human health world-wide.” 

 

Read the full press release here.

Read the fill article: Gilbert et al. 2017 Science Advances DOI: https://doi.org/10.1126/sciadv.1700898


First steps towards an effective treatment for the common cold

Antimicrobial peptides (AMPs) are oligopeptides, found in all living organisms, that form an integral part of the innate immune system, and can target a wide variety of bacteria, virus, fungi and parasites. Cathelicidins are a type of AMP. Humans poses only one cathelicidin, LL-37, which has previously been shown to have antiviral activity against numerous viruses including Influenza A, HIV-1, HSV and Vaccinia virus.  New research, conducted by a team at Edinburgh Napier University and recently published in Peptides, has demonstrated that LL-37 also has 'potent antiviral activity towards Human Rhinovirus' (HRV). This virus is responsible for many respiratory tract infections, for example the common cold, but can also underlie asthma and chronic obstructive pulmonary disease attacks, severe bronchiolitis and pneumonia.

In addition to LL-37, ovine cathelicidin SMAP-29 and porcine cathelicidin Protegrin-1 were also shown to reduce HRV replication in airway epithelial cells in vitro. The group demonstrated that the AMPs directly act on the virus, rather than just inducing apoptosis or necroptosis of the infected cells as others were seen to do. However, as AMPs are also known to alter cytokine and inflammatory processes, inflammation attenuation needs to be further investigated as a possible causal mechanism.

Lead researcher Dr Peter Barlow, Associate Professor of Immunology & Infection at Edinburgh Napier, and Secretary of the BSI Inflammation Affinity Group said: “This is an exciting discovery and our next steps will be to modify the peptide to make it even better at killing this virus. This research is still in the early stages, but we will ultimately be looking to develop drug treatments that have the potential to cure the common cold.” 

 

Read the full press release here.

Read the full article: Sousa et al. 2017 Peptides DOI: https://doi.org/10.1016/j.peptides.2017.07.013