Staphylococcusaureusα-Toxin Response Distinguishes Respiratory Virus–Methicillin-ResistantS. aureusCoinfection in Children

Yu, Karl O. A.; Randolph, Adrienne G.; Agan, Anna A.; Yip, Wai Ki; Truemper, Edward J.; Weiss, Scott L.; Ackerman, Kate G.; Schwarz, Adam; Giuliano, John S.; Hall, Mark W.; Wardenburg, Juliane Bubeck

doi:10.1093/infdis/jiw441

Cited by 20 publications

(17 citation statements)

References 26 publications

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“…To our knowledge, we provide the first in vivo evidence here that alpha-toxin-induced damage is critically responsible for acute animal death during coinfection, despite antibiotic treatment. These data are in agreement with those from a study by Yu et al, in which they demonstrated a correlation between alpha-toxin exposure and a worsened disease outcome in children with influenza-complicated MRSA pneumonia (11).…”

Section: Discussionsupporting

confidence: 93%

“…On the other hand, the role of this toxin in influenza virus/S. aureus coinfection remains uncertain (11). This is likely due to the fact that the reported animal models are not sensitive enough to discern the role of specific virulence factors in coinfection (19)(20)(21).…”

Section: Discussionmentioning

confidence: 99%

“…It has been shown that alpha-toxin directly disrupts the epithelial barrier and induces mortality, whereas its neutralization mitigates disease in animals (9,10). However, the role of alpha-toxin in influenza virus and S. aureus coinfection remains uncertain (11). To our knowledge, no study has hitherto examined the influence of alpha-toxin on antibiotic efficacy during the treatment of secondary MRSA pneumonia that occurs after influenza.…”

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confidence: 99%

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Linezolid Attenuates Lethal Lung Damage during Postinfluenza Methicillin-Resistant Staphylococcus aureus Pneumonia

et al. 2019

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Postinfluenza methicillin-resistant Staphylococcus aureus (MRSA) infection can quickly develop into severe, necrotizing pneumonia, causing over 50% mortality despite antibiotic treatments. In this study, we investigated the efficacy of antibiotic therapies and the impact of S. aureus alpha-toxin in a model of lethal influenza virus and MRSA coinfection. We demonstrate that antibiotics primarily attenuate alpha-toxin-induced acute lethality, even though both alpha-toxin-dependent and -independent mechanisms significantly contribute to animal mortality after coinfection. Furthermore, we found that the protein synthesis-suppressing antibiotic linezolid has an advantageous therapeutic effect on alpha-toxin-induced lung damage, as measured by protein leak and lactate dehydrogenase (LDH) activity. Importantly, using a Panton-Valentine leucocidin (PVL)-negative MRSA isolate from patient sputum, we show that linezolid therapy significantly improves animal survival from postinfluenza MRSA pneumonia compared with vancomycin treatment. Rather than improved viral or bacterial control, this advantageous therapeutic effect is associated with a significantly attenuated proinflammatory cytokine response and acute lung damage in linezolid-treated mice. Together, our findings not only establish a critical role of alpha-toxin in the extreme mortality of secondary MRSA pneumonia after influenza but also provide support for the possibility that linezolid could be a more effective treatment than vancomycin to improve disease outcomes.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Linezolid Attenuates Lethal Lung Damage during Postinfluenza Methicillin-Resistant Staphylococcus aureus Pneumonia

et al. 2019

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“…Interestingly, it was only when both platelets and myeloid cells lacked ADAM10 that an improvement in mortality was observed, suggesting the involvement of myeloid cells in addition to platelets at lethal doses of bacteria. Using a non-lethal dose of S. aureus , revealed that AT caused thrombosis and DIC rather than overt hemorrhage, but liver injury was still observed (Yu et al, 2016). Collectively, these results confirm that AT is a key virulence determinant in S. aureus sepsis and demonstrates the role of AT in liver injury associated with sepsis.…”

Section: Discussionmentioning

confidence: 99%

α-Toxin Induces Platelet Aggregation and Liver Injury during Staphylococcus aureus Sepsis

Surewaard

Thanabalasuriar

Zeng

et al. 2018

Cell Host & Microbe

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113

116

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During sepsis, small blood vessels can become occluded by large platelet aggregates of poorly understood etiology. During Staphylococcal aureus infection, sepsis severity is linked to the bacterial α-toxin (α-hemolysin, AT) through unclear mechanisms. In this study, we visualized intravascular events in the microcirculation and found that intravenous AT injection induces rapid platelet aggregation, forming dynamic micro-thrombi in the microcirculation. These aggregates are retained in the liver sinusoids and kidney glomeruli, causing multi-organ dysfunction. Acute staphylococcal infection results in sequestration of most bacteria by liver macrophages. Platelets are initially recruited to these macrophages and help eradicate S. aureus. However, at later time points, AT causes aberrant and damaging thrombosis throughout the liver. Treatment with an AT neutralizing antibody (MEDI4893) prevents platelet aggregation and subsequent liver damage, without affecting the initial and beneficial platelet recruitment. Thus, AT neutralization may represent a promising approach to combat staphylococcal-induced intravascular coagulation and organ dysfunction.

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“…Viruses, even those associated with outbreaks of severe adenovirus pneumonia, are rarely the sole cause of NP [72]. In contrast, the association of respiratory syncytial virus (RSV) and influenza virus infections with increased nasopharyngeal colonization by pneumococci and S. aureus and greater risk of secondary bacterial CAP with enhanced severity is well recognized [73][74][75][76][77]. However, few studies of NP in children have collected information on respiratory viruses.…”

Section: Microbiologymentioning

confidence: 99%

Necrotizing pneumonia: an emerging problem in children?

2017

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BackgroundIn children, necrotizing pneumonia (NP) is an uncommon, severe complication of pneumonia. It is characterized by destruction of the underlying lung parenchyma resulting in multiple small, thin-walled cavities and is often accompanied by empyema and bronchopleural fistulae.ReviewNP in children was first reported in children in 1994, and since then there has been a gradual increase in cases, which is partially explained by greater physician awareness and use of contrast computed tomography (CT) scans, and by temporal changes in circulating respiratory pathogens and antibiotic prescribing. The most common pathogens detected in children with NP are pneumococci and Staphylococcus aureus. The underlying disease mechanisms are poorly understood, but likely relate to multiple host susceptibility and bacterial virulence factors, with viral–bacterial interactions also possibly having a role. Most cases are in previously healthy young children who, despite adequate antibiotic therapy for bacterial pneumonia, remain febrile and unwell. Many also have evidence of pleural effusion, empyema, or pyopneumothorax, which has undergone drainage or surgical intervention without clinical improvement. The diagnosis is generally made by chest imaging, with CT scans being the most sensitive, showing loss of normal pulmonary architecture, decreased parenchymal enhancement and multiple thin-walled cavities. Blood culture and culture and molecular testing of pleural fluid provide a microbiologic diagnosis in as many as 50% of cases. Prolonged antibiotics, draining pleural fluid and gas that causes mass effects, and maintaining ventilation, circulation, nutrition, fluid, and electrolyte balance are critical components of therapy. Despite its serious nature, death is uncommon, with good clinical, radiographic and functional recovery achieved in the 5–6 months following diagnosis. Increased knowledge of NP’s pathogenesis will assist more rapid diagnosis and improve treatment and, ultimately, prevention.ConclusionIt is important to consider that our understanding of NP is limited to individual case reports or small case series, and treatment data from randomized-controlled trials are lacking. Furthermore, case series are retrospective and usually confined to single centers. Consequently, these studies may not be representative of patients in other locations, especially when allowing for temporal changes in pathogen behaviour and differences in immunization schedules and antibiotic prescribing practices.

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Staphylococcusaureusα-Toxin Response Distinguishes Respiratory Virus–Methicillin-ResistantS. aureusCoinfection in Children

Cited by 20 publications

References 26 publications

Linezolid Attenuates Lethal Lung Damage during Postinfluenza Methicillin-Resistant Staphylococcus aureus Pneumonia

Linezolid Attenuates Lethal Lung Damage during Postinfluenza Methicillin-Resistant Staphylococcus aureus Pneumonia

α-Toxin Induces Platelet Aggregation and Liver Injury during Staphylococcus aureus Sepsis

Necrotizing pneumonia: an emerging problem in children?

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