Open questions in the social lives of viruses.

Social interactions among viruses occur whenever multiple viral genomes infect the same cells, hosts, or populations of hosts. Viral social interactions range from cooperation to conflict, occur throughout the viral world, and affect every stage of the viral lifecycle. The ubiquity of these social interactions means that they can determine the population dynamics, evolutionary trajectory, and clinical progression of viral infections. At the same time, social interactions in viruses raise new questions for evolutionary theory, providing opportunities to test and extend existing frameworks within social evolution. Many opportunities exist at this interface: Insights into the evolution of viral social interactions have immediate implications for our understanding of the fundamental biology and clinical manifestation of viral diseases. However, these opportunities are currently limited because evolutionary biologists only rarely study social evolution in viruses. Here, we bridge this gap by (1) summarizing the ways in which viruses can interact socially, including consequences for social evolution and evolvability; (2) outlining some open questions raised by viruses that could challenge concepts within social evolution theory; and (3) providing some illustrative examples, data sources, and conceptual questions, for studying the natural history of social viruses.

Partial privatization and cooperation in biofilms.

The evolution of cooperation in microbes is a challenge to explain because microbes producing costly goods for the benefit of any strain types (cooperators) often withstand the threat of elimination by interacting with individuals that exploit these benefits without contributing (defectors). Here we developed an individual-based model to investigate whether partial privatization via the partial secretion of goods can favor cooperation in structured, surface-attaching microbial populations, biofilms. Whether partial secretion can favor cooperation in biofilms is unclear for two reasons. First, while partial privatization has been shown to foster cooperation in unstructured populations, little is known about the role of partial privatization in biofilms. Second, while limited diffusion of goods favors cooperation in biofilms because molecules are more likely to be shared with genetically-related individuals, partial secretion reduces goods that could have been directed towards genetically related individuals. Our results show that although partial secretion weakens the role that limited diffusion has on fostering cooperation, partial secretion favors cooperation in biofilms. Overall, our results provide predictions that future experiments could test to reveal contributions of relatedness and partial secretion to the social evolution of biofilms.

Spinal cord injury-related thermoregulatory impairment masks a fatal malignant hyperthermia crisis: a case report.

PURPOSE: Malignant hyperthermia (MH) is a hypermetabolic disorder that can occur in genetically susceptible individuals exposed to halogenated anesthetics and succinylcholine. Spinal cord injury (SCI) above the sixth thoracic vertebra is associated with dysfunction of the sympathetic/parasympathetic nervous pathways, including thermoregulatory dysfunction, presenting as hypothermia in cold environments because of vasodilation and heat loss. This effect could mitigate or obscure an MH episode. Here, we describe development of a fatal MH crisis in a patient with SCI. CLINICAL FEATURES: A 27-yr-old male patient with an SCI after fracture of the sixth cervical vertebra was admitted for spinal arthrodesis. Anesthetic medications included remifentanil, propofol, succinylcholine, rocuronium, and isoflurane. After the start of the surgery, muscular contractures resembling myoclonus were noted, which resolved with pancuronium administration. Four hours after the start of anesthesia, the patient presented with hyperthermia, hypercarbia, hypotension, muscle rigidity, arrhythmia, and cardiogenic shock, with metabolic/respiratory acidosis. Malignant hyperthermia was suspected and the treatment was started, but he developed cardiopulmonary arrest and died an hour and a half after the first cardiac arrest. Both parents were investigated and were found to have normal creatine kinase levels and positive in vitro contracture tests. His mother carried a variant in the ryanodine receptor type 1 (RYR1) gene (c.14918C>T), which is associated with MH. CONCLUSION: Spinal cord injury-induced thermoregulatory dysfunction may obscure the early diagnosis of MH and lead to fatal outcome.

RéSUMé: OBJECTIF: L'hyperthermie maligne est un trouble hypermétabolique qui peut survenir chez les personnes génétiquement susceptibles exposées à des anesthésiques volatils et à la succinylcholine. Les lésions médullaires situées au-dessus de la sixième vertèbre thoracique sont associées à un dysfonctionnement des voies nerveuses sympathiques / parasympathiques, y compris un trouble de la thermorégulation, et se présentent sous forme d'hypothermie dans des environnements froids en raison de la vasodilatation et de la perte de chaleur. Cet effet pourrait atténuer ou occulter un épisode d'hyperthermie maligne. Nous décrivons ici l'apparition d'une crise mortelle d'hyperthermie maligne chez un patient atteint de lésion médullaire. CARACTéRISTIQUES CLINIQUES: Un patient de 27 ans atteint d'une lésion médullaire après une fracture de la sixième vertèbre cervicale a été admis pour une arthrodèse rachidienne. Les médicaments anesthésiques comprenaient du rémifentanil, du propofol, de la succinylcholine, du rocuronium et de l'isoflurane. Après le début de la chirurgie, des contractures musculaires ressemblant à une myoclonie ont été notées, lesquelles se sont résolues avec l'administration de pancuronium. Quatre heures après l'induction d'anesthésie, le patient a présenté une hyperthermie, une hypercarbie, une hypotension, une rigidité musculaire, une arythmie et un choc cardiogénique, avec acidose métabolique / respiratoire. Une hyperthermie maligne a été suspectée et le traitement a été amorcé, mais le patient a subi un arrêt cardiorespiratoire et est décédé une heure et demie après le premier arrêt cardiaque. Les deux parents ont passés des tests et se sont avérés avoir des taux normaux de créatine kinase et des tests de contracture in vitro positifs. La mère du patient était porteuse d'un variant du gène récepteur de ryanodine de type 1 (RYR1) (c.14918C>T), lequel est associé à l'hyperthermie maligne. CONCLUSION: Un trouble de la thermorégulation induit par une lésion médullaire peut masquer un diagnostic précoce d'hyperthermie maligne et entraîner une issue fatale.

Sarcoglycanopathies: an update.

Sarcoglycanopathies are the most severe forms of autosomal recessive limb-girdle muscular dystrophies (LGMDs), constituting about 10-25% of LGMDs. The clinical phenotype is variable, but onset is usually in the first decade of life. Patients present muscle hypertrophy, elevated CK, variable muscle weaknesses, and progressive loss of ambulation. Four subtypes are known: LGMDR3, LGMDR4, LGMDR5 and LGMDR6, caused, respectively, by mutations in the SGCA, SGCB,SGCG and SGCD genes. Their four coded proteins, α-SG, ß-SG, λ-SG and δ-SG are part of the dystrophin-glycoprotein complex (DGC) present in muscle sarcolemma, which acts as a linker between the cytoskeleton of the muscle fiber and the extracellular matrix, providing mechanical support to the sarcolemma during myofiber contraction. Many different mutations have already been identified in all the sarcoglycan genes, with a predominance of some mutations in different populations. The diagnosis is currently based on the molecular screening for these mutations. Therapeutic approaches include the strategy of gene replacement mediated by a vector derived from adeno-associated virus (AAV). Pre-clinical studies have shown detectable levels of SG proteins in the muscle, and some improvement in the phenotype, in animal models. Therapeutic trials in humans are ongoing.

Altered in vitro muscle differentiation in X-linked myopathy with excessive autophagy.

X-linked myopathy with excessive autophagy (XMEA) is a genetic disease associated with weakness of the proximal muscles. It is caused by mutations in the VMA21 gene, coding for a chaperone that functions in the vacuolar ATPase (v-ATPase) assembly. Mutations associated with lower content of assembled v-ATPases lead to an increase in lysosomal pH, culminating in partial blockage of macroautophagy, with accumulation of vacuoles of undigested content. Here, we studied a 5-year-old boy affected by XMEA, caused by a small indel in the VMA21 gene. Detection of sarcoplasmic Lc3 (also known as MAP1LC3B)-positive vacuoles in his muscle biopsy confirmed an autophagy defect. To understand how autophagy is regulated in XMEA myogenesis, we used patient-derived muscle cells to evaluate autophagy during in vitro muscle differentiation. An increase in lysosomal pH was observed in the patient's cells, compatible with predicted functional defect of his mutation. Additionally, there was an increase in autophagic flux in XMEA myotubes. Interestingly, we observed that differentiation of XMEA myoblasts was altered, with increased myotube formation observed through a higher fusion index, which was not dependent on lysosomal acidification. Moreover, no variation in the expression of myogenic factors nor the presence of regenerating fibers in the patient's muscle were observed. Myoblast fusion is a tightly regulated process; therefore, the uncontrolled fusion of XMEA myoblasts might generate cells that are not as functional as normal muscle cells. Our data provide new evidence on the reason for predominant muscle involvement in the context of the XMEA phenotype.This article has an associated First Person interview with the first author of the paper.

Faster regeneration associated to high expression of Fam65b and Hdac6 in dysferlin-deficient mouse.

Dysferlin is a sarcolemmal muscle protein associated with the processes of membrane repair, trafficking, and fusion of intracellular vesicles and muscle regeneration. Mutations in the DYSF gene cause clinically distinct forms of muscular dystrophies. The dysferlin-deficient SJL/J mouse model presents a reduction of 85% of the protein but shows mild weakness and discrete histopathological alterations. To study the effect of dysferlin deficiency in the muscle regenerative process, we used a model of electrical injury by electroporation to induce muscle degeneration/regeneration in the SJL/J mouse. The relative expression of the genes Pax7, MyoD, Myf5, and Myog was accompanied by the histopathological evaluation during muscle recovery at different time points after injury. We also investigated the effects of dysferlin deficiency in the expression of genes encoding FAM65B and HDAC6 proteins, recently described as forming a tricomplex with dysferlin at the beginning of myoblast differentiation. We observed an altered time course through the process of degeneration and regeneration in dysferlin-deficient mice, with remarkable regenerative capacity characterized by a faster and effective response in the first days after injury, as compared to the WT mice. Also, dysferlin deficiency seems to significantly alter the gene expression of Fam65b and Hdac6 during regeneration, since higher levels of expression of both genes were observed in dysferlin-deficient mice. These results need further attention to define their relevance in the disease mechanism.

Muscle satellite cells and impaired late stage regeneration in different murine models for muscular dystrophies.

Satellite cells (SCs) are the main muscle stem cells responsible for its regenerative capacity. In muscular dystrophies, however, a failure of the regenerative process results in muscle degeneration and weakness. To analyze the effect of different degrees of muscle degeneration in SCs behavior, we studied adult muscle of the dystrophic strains: DMDmdx, Largemyd, DMDmdx/Largemyd, with variable histopathological alterations. Similar results were observed in the dystrophic models, which maintained normal levels of PAX7 expression, retained the Pax7-positive SCs pool, and their proliferation capacity. Moreover, elevated expression of MYOG, an important myogenic factor, was also observed. The ability to form new fibers was verified by the presence of dMyHC positive regenerating fibers. However, those fibers had incomplete maturation characteristics, such as small and homogenous fiber caliber, which could contribute to their dysfunction. We concluded that dystrophic muscles, independently of their degeneration degree, retain their SCs pool with proliferating and regenerative capacities. Nonetheless, the maturation of these new fibers is incomplete and do not prevent muscle degeneration. Taken together, these results suggest that the improvement of late muscle regeneration should better contribute to therapeutic approaches.