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.
Pulling the fire alarm against lung infections
Researchers from the University of Edinburgh’s MRC Centre for Inflammation Research have found that a molecule called LL37 affects immune responses to Pseudomonas aeruginosa infection.
P. aeruginosa is a multi-drug resistant bacteria that causes opportunistic infections in immunocompromised patients. Lung infections are responsible for 1 in 5 deaths in the UK, and many pathogens are becoming increasingly drug-resistant. Researchers hope that being able to modulate the immune system will offer a non-antibiotic based treatment for these infections.
LL37 is an antimicrobial host defence peptide that is produced in response to several non-specific threats such as infection, damage, or inflammation. It affects the host response to bacterial and viral pulmonary infections by activating an inflammatory immune response. Infected cells take up LL37, which signals to the NLRP3 inflammasome to activate caspase 1. Caspase 1 produces inflammatory immune signals that attract neutrophils to the site of infection, and encourages infected cells to kill themselves.
Apoptosis of infected cells helps protect uninfected cells from being infected. An early inflammatory response is associated with improved immune clearance of the pathogen.
Professor Donald Davidson, who led the study published in PLOS Pathogens, said, “Our search for alternative and complementary treatments for antibiotic-resistant infections is becoming ever more urgent. Trying to boost the best of the human body’s effective natural defences, like this, may prove to be an important part of our future solutions.”
Infiltrating the basement membrane
Researchers from the University of Bristol have discovered how inflammatory cells are able to gain access to cancer cells in epithelial tissues in a study published in Cell Reports. Using translucent zebrafish as a model, researchers used correlative light and electron microscopy to visualise how inflammatory cells such as macrophages and neutrophils are able to use micro-perforations in the basement membrane to enter the epithelium and contact cancer cells.
Inflammatory cells are known to encourage cancer malignancy, but it was unclear how they were reaching the nascent cancers. The team led by Professor Paul Martin discovered that the cancer cells nearest the micro-perforations had more contact with immune cells, so grew fastest. The growth of the tumours led to an increase in the size of the holes in the basement membrane.
It is believed that, in healthy skin, the micro-perforations could be used for immune surveillance. Similar breaches have been reported in human airways and guts, and may allow immune cells access in the same manner as the zebrafish. The findings have important clinical applications, as they have identified another stage at which cancer malignancy may be able to be halted. Further research is needed before this could be used for a treatment, but the researchers are optimistic.
Professor Martin explained the impact of the work, "This 'window' on the cancer process has revealed ‘weak spots’ in the barrier layer that inflammatory cells must breach in order to access and feed the cancer cells within the skin. Now we know these micro-perforations exist we can target them with cancer therapeutics.”
Understanding maternal protection of newborns
Antibodies are passed from the mother to the foetus in the womb. This transfers some of the mother’s immunity to the baby, and helps protect the infant before they can be vaccinated. A study based at the Ragon Institute of Massachusetts General Hospital, MIT and Harvard has discovered a mechanism for the regulation of maternal antibody transfer. Using a technique called systems serology, researchers discovered that not all antibodies are transferred equally across the placenta. For example, measles antibodies are very efficiently transferred, while poliovirus antibodies are not.
By comparing the quality and quantity of antibodies in maternal blood samples to the umbilical cord, the team discovered that antibodies which activate NK cells are selectively transferred. The placenta has a ‘sieve’ that chooses which antibodies are transferred based on Fc qualities such as glycosylation. Digalactosylated Fc glycans are preferentially transferred to the foetus.
The study published in Cell Reports found that the antibodies that were transferred were potent activators of neonatal NK cells. Newborn immune systems are immature, but NK cells are the most responsive part of the newborn immune system. The antibodies were able to drive NK degranulation at equivalent levels in maternal blood and the umbilical cord.
Improved knowledge of antibody transfer may improve future vaccine design. Co-senior author of the paper Dr Laura Riley hopes that, "We will now have the opportunity to create better maternal vaccines and deliver them at the ideal time during pregnancy to maximally protect newborns when they are most vulnerable." Researchers are now aiming to encourage altered glycosylation of the Fc portion of the antibodies raised against a vaccine to promote transfer.
Engineering your friendly bacteria
Published in the BSI’s official journal Clinical & Experimental Immunology, this month’s Editors Choice comes from the lab of BSI member Simon Carding at the Quadram Institute.
The plague bacterium Yersinia pestis is still endemic in some parts of the world, and there is currently no vaccine against it. Professor Carding hopes to change that by expressing plague antigens on stable microvesicles derived from harmless human commensal bacteria. The microvesicles can express two different antigens, called V and F, to ensure a broad immune response, without any adverse effects in animal studies.
These engineered microvesicles were able to deliver the vaccine directly to the sites of plague infection in non-human primates, and are less reliant on a cold chain than traditional injected vaccines. Microvesicles expressing the V antigen were particularly successful at inducing production of two different types of antibody in the serum and at mucosal surfaces. The microvesicles can also be made quickly with relatively inexpensive technology, that is already used for Meningitis B vaccines.
There are no whole cells in this vaccine, while the microvesicles are naturally attractive to the immune system, so the vaccine is completely non-infectious and does not require adjuvants such as aluminium. The authors are hopeful that this new vaccine method could be used to cut costs of mass vaccination programmes, as needle-free delivery and thermostability cut out two of the biggest challenges. The results are promising, but this is just a first step. Clinical trials will be needed to test if the vaccine is safe and effective in humans.
Read the full article: Carvalho et al. 2019 Clinical & Experimental Immunology DOI: https://doi.org/10.1111/cei.13301