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.
Common ground in Parkinson’s and TB pathogenesis
The gene LRRK2 encodes a type of protein enzyme called a kinase. Gene mutations that cause over-activity of this enzyme are associated with increased susceptibility to mycobacterial infections, such as tuberculosis (TB), as well as Parkinson’s disease. Although drugs that block LRRK2 function are proving to be a promising treatment for Parkinson's, until now scientists have been in the dark about how LRRK2 mutations contribute to its pathology in the disease as well as its role tuberculosis susceptibility.
Normally, immune cells called macrophages engulf or ‘eat’ biological debris such as cellular proteins and bacteria, and get rid of them by 'digesting' them in cellular compartments called phagolysosomes. As published this month in The EMBO Journal, a team of researchers, led by Dr Maximiliano Gutierrez from the Francis Crick Institute and BSI member Professor Matthias Trost from Newcastle University, showed that mutations in LRRK2 prevented cellular digestion of TB-causing mycobacteria after being eaten by macrophages. This resulted in an increase in the survival of bacteria and less control over their replication. When the LRRK2 gene was deleted from macrophages in both mice and humans, replication of mycobacteria in these cells was restricted and the spread of infection in mice was reduced.
As well as providing new insight into why LRRK2 mutations increase TB susceptibility, the teams now think that increased activity of a mutated form of LRRK2 may also result in a lack of immune clearance of cellular proteins, leading to the development of Parkinson’s disease. Joint first author and BSI member Dr Susanne Herbst explained: “We think that this mechanism might also be at play in Parkinson's disease, where abnormal masses of protein called 'Lewy bodies' build up in neurons in the brain and cause damage. By studying TB, we have found a possible explanation for why LRRK2 mutations are a genetic risk factor for Parkinson's disease.” Co-senior author, Professor Trost, added: “Our data implies that the conserved machinery that cells use to destroy and degrade external particles such as bacteria and damaged neurons is an important target for drug discovery”, indicating that their findings may lead to better treatments for both TB and Parkinson’s.
Read the press release here.
Read the full article here: Härtlova et al. 2018 The EMBO Journal DOI: https://doi.org/10.15252/embj.201798694
Expanding the toolkit of flu immunity
Influenza A infection is a major cause of human mortality and morbidity. It is highly infectious between humans, yet can also infect birds and pigs. Pigs can be infected with human, avian and swine influenza, rendering them a ‘mixing vessel’ whereby genetic reassortment between different types of influenza can produce highly virulent new strains that humans are not immune to.
Pigs are a good model in which to study influenza vaccines as their lung anatomy and immunology is similar to humans. Thus, scientists may be able to discover more effective vaccines for both species, which may go some way to preventing the spread of virulent new strains of influenza from pigs to humans.
A key challenge in pig-based vaccine research against influenza has been an inability to look at specific cellular immune responses to influenza vaccines and/or viruses due to a lack of biological tools. Following a cross-institute collaboration, scientists from Cardiff University, The Pirbright Institute and the University of Bristol have developed a way of identifying the specific immune cells, called cytotoxic (cell-killing) T cells, in pigs which are involved in immunity to influenza or its potential vaccine. Published in the journal Plos Pathogens, the teams used this method to study the efficacy of a vaccine candidate which had the potential to protect against all influenza viruses. The team found that the aerosol-delivered vaccine induced large numbers of cytotoxic T cells in the respiratory tract that could specifically attack influenza.
Lead author and BSI member Professor Andrew Sewell of Cardiff University explained: "Pigs provide a very good model system for influenza virus infection. They can be infected with both human and bird flu in addition to swine flu and are known to act as important 'mixing vessels' for the creation of pandemic flu strains. The new tools we’ve developed in Cardiff will allow researchers at Pirbright, the Bristol Veterinary School and elsewhere to closely study pig T cell responses to influenza for the first time. The ultimate goal will be to create a vaccine that can be effective against all strains of flu in pigs, birds and humans.”
Read the press release here.
Read the full article here: Tungatt et al. 2018 Plos Pathogens DOI: https://doi.org/10.1371/journal.ppat.1007017
Putting the heat on infections and tumours
A key symptom of a systemic infection such as flu is an increase in body temperature, or fever. However, up until now the direct immunological role of heat during an infection has been unclear. A multidisciplinary team of biologists and mathematicians led by BSI member Professor Mike White at The University of Manchester and Professor David Rand at the University of Warwick set out to elucidate this connection by measuring the activity of a gene-regulating protein called NFκB in human and mouse cells at different temperatures.
In a paper published in the journal PNAS, scientists incubated human and mouse cells between 37°C and 40°C - temperatures commonly seen during a fever. The cells were also stimulated by a proinflammatory molecule called TNFα, which is often released during an infection. Scientists then used fluorescent proteins to live-track the cellular movements of NFκB and found that higher temperatures led to its earlier activation. In turn, this allowed for faster regulation of the genes involved in the response to inflammatory signals from infections or tumours. Conversely, a reduction in temperature – down to 34°C – delayed the activation of NFκB, effectively making the cells slower to respond to these inflammatory signals.
Professor Mike White elaborated on this: “We have known for some time that influenza and cold epidemics tend to be worse in the winter when temperatures are cooler. Also, mice living at higher temperatures suffer less from inflammation and cancer. These changes may now be explained by altered immune responses at different temperatures.”
As body temperature decreases slightly as we sleep, the teams also speculated that chronic inflammation and worsened cancer prognoses could be partially due to disrupted sleep/wake cycles, such as that seen in shift work.
Read the press release here.
Read the full article here: Harper et al. 2018 PNAS DOI: https://doi.org/101.1073/pnas/1803609115