Poly-adenosine diphosphate-ribose polymerases (PARPs) promote ADP-ribosylation, a highly conserved, fundamental posttranslational modification (PTM). PARP catalytic domains transfer the ADP-ribose moiety from NAD+ to amino acid residues of target proteins, leading to mono- or poly-ADP-ribosylation (MARylation or PARylation). This PTM regulates various key biological and pathological processes. In this review, we focus on the roles of the PARP family members in inflammation and host–pathogen interactions. Here we give an overview the current understanding of the mechanisms by which PARPs promote or suppress proinflammatory activation of macrophages, and various roles PARPs play in virus infections. We also demonstrate how innovative technologies, such as proteomics and systems biology, help to advance this research field and describe unanswered questions.

All coronaviruses (CoVs) contain a macrodomain, also termed Mac1, in non-structural protein 3 (nsp3) which binds and hydrolyzes mono-ADP-ribose (MAR) covalently attached to proteins. Despite several reports demonstrating that Mac1 is a prominent virulence factor, there is still a limited understanding of its cellular roles during infection. Currently, most of the information regarding the role of CoV Mac1 during infection is based on a single point mutation of a highly conserved asparagine residue, which makes contact with the distal ribose of ADP-ribose. To determine if additional Mac1 activities contribute to CoV replication, we compared the replication of murine hepatitis virus (MHV) Mac1 mutants, D1329A and N1465A, to the previously mentioned asparagine mutant, N1347A. These residues contact the adenine and proximal ribose in ADP-ribose, respectively. N1465A had no effect on MHV replication or pathogenesis, while D1329A and N1347A both replicated poorly in bone-marrow derived macrophages (BMDMs), were inhibited by PARP enzymes, and were highly attenuated in vivo. Interestingly, D1329A was also significantly more attenuated than N1347A in all cell lines tested. Conversely, D1329A retained some ability to block IFN-β transcript accumulation compared to N1347A, indicating that these mutations have different effects on Mac1 functions. Combining these two mutations resulted in a virus that was unrecoverable, suggesting that the combined activities of Mac1 may be essential for MHV replication. We conclude that Mac1 has multiple functions that promote the replication of MHV, and that these results provide further evidence that Mac1 could be a prominent target for anti-CoV therapeutics. IMPORTANCE In the wake of the COVID-19 epidemic, there has been a surge to better understand how CoVs replicate, and to identify potential therapeutic targets that could mitigate disease caused by SARS-CoV-2 and other prominent CoVs. The highly conserved macrodomain, also termed Mac1, is a small domain within non-structural protein 3. It has received significant attention as a potential drug target as previous studies demonstrated that it is essential for CoV pathogenesis in multiple animal models of infection. However, the functions of Mac1 during infection remain largely unknown. Here, using targeted mutations in different regions of Mac1, we found that Mac1 has multiple functions that promote the replication of MHV, a model CoV, and therefore is more important for MHV replication than previously appreciated. These results will help guide the discovery of these novel functions of Mac1 and the development of inhibitory compounds targeting this domain.

Learning by experience involves being able to reflect on a personal happening and through a process of analysis, come to understand it. Such an activity should result in ‘deep learning’ when carried out in a structured way. Higher education establishments are keen to develop such learning methods in students, as a secondary effect of this form of learning is to create student independence from the teacher. This is a much sought after ability as recent government changes have meant higher student numbers without a corresponding rise in teacher numbers. This threatens the quality of student knowledge unless it is compensated for in some way. This study sets out to examine the learning of two student groups. The experimental design was that of group comparison using matched pairs of students. One group, the experimental group, were exposed to reflective teaching methods, whilst the other group (the control group) were exposed to conventional teaching methods only. At the end of a set period of time, the learning achieved in both groups was estimated using an especially designed test paper. The results obtained from both groups were compared and it was found that there was no significant difference obtained in the learning between the groups (P>5%) Therefore, we concluded that students learnt just as well using reflective methods when compared to the conventional methods of learning. However, the potential for enhancement of learning was evident and invites further investigation. All the students in this study were on the Diploma in Higher Education (Nursing) course. The subject area used throughout the study was in the biological sciences.

Learning by experience involves being able to reflect on a personal happening and through a process of analysis, come to understand it. Such an activity should result in 'deep learning' when carried out in a structured way. Higher education establishments are keen to develop such learning methods in students, as a secondary effect of this form of learning is to create student independence from the teacher. This is a much sought after ability as recent government changes have meant higher student numbers without a corresponding rise in teacher numbers. This threatens the quality of student knowledge unless it is compensated for in some way. This study sets out to examine the learning of two student groups. The experimental design was that of group comparison using matched pairs of students. One group, the experimental group, were exposed to reflective teaching methods, whilst the other group (the control group) were exposed to conventional teaching methods only. At the end of a set period of time, the learning achieved in both groups was estimated using an especially designed test paper. The results obtained from both groups were compared and it was found that there was no significant difference obtained in the learning between the groups (P>5%) Therefore, we concluded that students learnt just as well using reflective methods when compared to the conventional methods of learning. However, the potential for enhancement of learning was evident and invites further investigation. All the students in this study were on the Diploma in Higher Education (Nursing) course. The subject area used throughout the study was in the biological sciences.

Several coronavirus (CoV) encoded proteins are being evaluated as targets for antiviral therapies for COVID-19. Included in this set of proteins is the conserved macrodomain, or Mac1, an ADP-ribosylhydrolase and ADP-ribose binding protein. Utilizing point mutant recombinant viruses, Mac1 was shown to be critical for both murine hepatitis virus (MHV) and severe acute respiratory syndrome (SARS)-CoV virulence. However, as a potential drug target, it is imperative to understand how a complete Mac1 deletion impacts the replication and pathogenesis of different CoVs. To this end, we created recombinant bacterial artificial chromosomes (BACs) containing complete Mac1 deletions (ΔMac1) in MHV, MERS-CoV, and SARS-CoV-2. While we were unable to recover infectious virus from MHV or MERS-CoV ΔMac1 BACs, SARS-CoV-2 ΔMac1 was readily recovered from BAC transfection, indicating a stark difference in the requirement for Mac1 between different CoVs. Furthermore, SARS-CoV-2 ΔMac1 replicated at or near wild-type levels in multiple cell lines susceptible to infection. However, in a mouse model of severe infection, ΔMac1 was quickly cleared causing minimal pathology without any morbidity. ΔMac1 SARS-CoV-2 induced increased levels of interferon (IFN) and interferon-stimulated gene (ISG) expression in cell culture and mice, indicating that Mac1 blocks IFN responses which may contribute to its attenuation. ΔMac1 infection also led to a stark reduction in inflammatory monocytes and neutrophils. These results demonstrate that Mac1 only minimally impacts SARS-CoV-2 replication, unlike MHV and MERS-CoV, but is required for SARS-CoV-2 pathogenesis and is a unique antiviral drug target.