Authors: Martha Powell, Future Science Group
2018 has seen many research highlights and we gave our Expert Panel the difficult challenge of picking their favorites and explaining why! Find out more about topics from improving pneumonia treatment to pre-exposure prophylaxis with their choices below.
Improving the care of pnuemonia
I think this very recent study is fascinating in terms of design and outcomes .
An issue with pneumonia is often in severe infections the patient’s own immune system can be as much a culprit as the invading pathogens. This was often exemplified in SARS cases.
The use of corticosteroids has been advocated but not shown to be of significant value. This study employs two quite distinct anti-inflammatory agents, aspirin and macrolide antibiotics.
The macrolide, although antibacterial, has been shown to have quite marked anti-inflammatory properties in respiratory infections. Although this study did not look for causality of the pneumonia it clearly demonstrated a positive outcome in the combination group. The addition of these two commonly used drugs to standard therapy could yield significant improvement in care of severe pneumonia.
Is it time to re-think Pre-Exposure Prophylaxis for HIV?
Pre-exposure prophylaxis (PrEP) is highly efficacious for preventing HIV. Apart from oral formulation for PrEP, there are increasing evidences that an approach with non-oral formulations would be safe and feasible.
A recent paper by Raphael Landovitz and colleagues reported the results of HPTN 077, a Phase IIa randomized controlled trial with long-acting (LA) injectable cabotegravir (CAB) via intramuscular (IM) administration .
In this study, CAB LA was well tolerated at the doses and dosing intervals used (800mg every 12 weeks in cohort 1 and 600mg every 8 weeks in cohort 2). Injection site reactions (ISRs) had been frequently observed, although determined few product discontinuations. CAB LA 600 mg every 8 weeks met prespecified pharmacokinetic targets for both male and female study participants.
Ten subjects discontinued CAB for adverse events and four severe adverse events occurred in CAB arms. Seven sexually transmitted infections (STIs) occurred in six study participants and one female subject acquired HIV 48 weeks after the final CAB injection with her plasma CAB concentration below the lower limit of quantification.
Administration of CAB, as therapeutic agent, is combined with IM rilpivirine, also known as TMC278, which has been also checked as prophylactic agent .
These papers focused on an alternative form of PReP and put more light on burning themes related to PReP, such as adherence levels, side effects, acceptability, and occurrence of STIs. Thus, a brilliant future is potentially ahead of us.
The role of pili in natural transformation
Natural transformation, which involves the uptake of free DNA, is a recognized mode of horizontal gene transfer among bacterial species. Whilst bacteria pili have been described as playing a role in transformation, the precise mechanism whereby this is achieved has hitherto remained unclear. In this paper, the authors have utilized a unique methodology for viewing these structures in live cells and provide the first description of the mechanism for type IV competence pilus-mediated DNA uptake during natural transformation .
The approach used to view the live cells which involved fluorescence labelling and real time microscopy is simple yet elegant and it enabled the researchers to follow the dynamics of the activities of the cellular structures under experimental conditions yielding significant new information. The findings show that the steps in natural transformation involve the binding of type IV competence pili to extracellular double-stranded DNA via their tip, followed by retraction of the pilus that brings the tip-bound DNA to the cell surface and is spatiotemporally associated with DNA internalization. The unique methodology described in this paper presents an approach that can be used for studying other live bacterial cells in a dynamic manner with the potential for providing novel insight into their nature and adaptations.
In the art of war, knowledge of the tactics of the enemy is a key determinant for victory. The process of horizontal gene transfer fosters the dissemination of antibiotic resistance genes and virulence factors. The methodology and findings from this study provides a key to unlocking this important bacterial tactic and represents a strategic potential in the war against antibiotic resistance.
Predictive modeling for influenza
As 2018 was the centenary year of the 1918 influenza pandemic, there were numerous publications reflecting on progress made in the surveillance and control of influenza A viruses. During the year, there was heightened emphasis on progress towards the holy grail of a universal influenza vaccine. A BBC documentary and the associated paper in Epidemics ‘Contagion! The BBC Four Pandemic – The model behind the documentary’ represented a fantastic example of citizen science in action .
However, for me, a review of the current state of predictive modeling of influenza was one of the most useful papers of the year . In providing an overview of the global human influenza surveillance program and vaccine strain selection process, it demonstrates how large-scale collaborative science can achieve a huge public health impact.
A bacterium’s enemy isn’t your friend.
Staphylococcus aureus can be a harmless bacterial resident of nasal, respiratory and reproductive tissue, but has also the potential to cause infections which can be deadly in immunocompromised hosts. Recurrent infections with this pathogen are common, suggesting that S. aureus is capable of evading pre-existing immunity. Complex host-microbial interactions likely play a role. Most humans have antibodies against S. aureus, but these are highly variable and often not protective for reasons poorly understood. Over the past decades strains of S. aureus termed methicillin-resistant S. aureus (MRSA) have emerged, which are resistant to treatment with methylated penicillin-based antibiotics, causing a serious health threat in those with a reduced immune defense.
A highlight from 2018 was the unexpected discovery by Gerlach and coworkers [7,8] of a previously unknown mechanism whereby viruses influence whether MRSA is recognized by the immune system. Their findings reveal a process that might tip the balance in determining whether this bacterium remains harmless or becomes disease-causing.
A large percentage of human antibodies are against S. aureus wall teichoid acids (WTA), made up of ribitol phosphate polymer that can constitute up to half of the cell wall mass. WTA is normally modified by an enzyme called TarS adding an N-acetylglucosamine (GlcNac) molecule to D-ribitol phosphate at a particular carbon atom known as C4. When investigating genome sequences of the prominent healthcare- and livestock-associated MRSA clones CC5 and CC398 for the presence of immune-evasion genes, Gerlach and colleagues found that a considerable proportion of these clones contain prophages that encode and alternative WTA glycosyltrasferase, namely TarP.
Structural analysis indicated that TarP transfers GlcNac to an alternative carbon atom, i.e. C3, having important consequences for immune recognition by antibodies. TarP-modified WTA is far less immunogenic in mice and is poorly recognized by human antisera, in comparison to TarS-modified WTA. If both enzymes are present TarP is dominant, meaning that GlcNac linkage is made on the C3 carbon rather than on the C4 carbon. This MRSA-associated change to the S. aureus cell wall reported by Gerlach et al is important for two reasons. First, it highlights that viruses (prophages) are a third party that can tip the fragile balance between the host defense and a resident microbe. Second, in a time that may be considered as the beginning of a ‘post-antibiotic era’ mechanistic insight into factors determining the effectiveness of the host immune response to S. aureus, especially MRSA, are crucial to develop new strategies to manage infection.
You might also like:
- Falcone M, Russo A, Shindo Y et al. Combination of aspirin plus macrolides in patients with severe community-acquired pneumonia: a hypothesis-generating study. Agents Chemo. doi:10.1128/AAC.01556-18 (2018).
- Landovitz RJ, Li S, Grinsztejn B, Dawood H et al. Safety, tolerability, and pharmacokinetics of long-acting injectable cabotegravir in low-risk HIV-uninfected individuals: HPTN 077, a phase 2a randomized controlled trial. PLoS Med. 15(11), e1002690 (2018).
- Bekker L-G, Li SS, Tolley B et al. HPTN 076: TMC278 LA safe, tolerable, and acceptable for HIV preexposure prophylaxis. 24th Conference on Retroviruses and Opportunistic Infections, Seattle, WA, USA, Feb 13–16 2017. Abstract 421LB.
- Ellison CK, Dalia TN, Vidal Ceballos A et al. Retraction of DNA-bound type IV competence pili initiates DNA uptake during natural transformation in Vibrio cholerae. Nat Microbiol. 3(7),773–780 (2018).
- Klepac P, Kissler S, Gog J. Contagion! The BBC Four Pandemic – The model behind the documentary Epidemics. 24, 49–59 (2018).
- Morris DH, Gostic KM, Pompei S et al. Predictive modeling of influenza shows the promise of applied evolutionary biology. Trends Microbiol. 26(2), 102–118 (2018).
- Gerlach D, Guo Y, De Castro C et al. Methicillin-resistant Staphylococcus aureus alters cell wall glycosylation to evade immunity. Nature 563, 705–709 (2018).
- Gilmore M, Gilmore MS. A bacterium’s enemy isn’t your friend. Nature 563, 637–638 (2018).