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Increased Fungal Infection Mortality Induced by Concurrent Viral Cellular Manipulations

  • REVIEW: CONCURRENT FUNGAL AND VIRAL INFECTIONS
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Abstract

Certain respiratory fungal pathogen mono-infections can cause high mortality rates. Several viral pathogen mono-infections, including influenza viruses and coronaviruses including SARS-CoV-2, can also cause high mortality rates. Concurrent infections by fungal pathogens and highly manipulative viral pathogens can synergistically interact in the respiratory tract to substantially increase their mortality rates. There are at least five viral manipulations which can assist secondary fungal infections. These viral manipulations include the following: (1) inhibiting transcription factors and cytokine expressions, (2) impairing defensive protein expressions, (3) inhibiting defenses by manipulating cellular sensors and signaling pathways, (4) inhibiting defenses by secreting exosomes, and (5) stimulating glucocorticoid synthesis to suppress immune defenses by inhibiting cytokine, chemokine, and adhesion molecule production. The highest mortality respiratory viral pandemics up to now have had substantially boosted mortalities by inducing secondary bacterial pneumonias. However, numerous animal species besides humans are also carriers of endemic infections by viral and multidrug-resistant fungal pathogens. The vast multi-species scope of endemic infection opportunities make it plausible that the pro-fungal manipulations of a respiratory virus can someday evolve to enable a very high mortality rate viral pandemic inducing multidrug-resistant secondary fungal pathogen infections. Since such pandemics can quickly spread world-wide and outrun existing treatments, it would be worthwhile to develop new antifungal treatments well before such a high mortality event occurs.

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Fig. 1

Front Immunol. 2021;12:756249. https://doi.org/10.3389/fimmu.2021.757249. This is licensed under Creative Commons CC-BY version 4 from Frontiers as the original publisher. Copyright © 2021 Sugrue, Bourke and O’Farrelly

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Data Availability

Not applicable.

Abbreviations

ALI:

Acute lung injury

AP-1:

Activator protein-1

ARDS:

Acute respiratory distress syndrome

BALF:

Bronchoalveolar lavage fluid

CAC:

COVID-19-associated candidiasis

CAM:

COVID-19-associated mucormycosis

CAP:

Community-acquired pneumonia

CAPA:

COVID-19-associated pulmonary aspergillosis

CMV:

Cytomegalovirus

CSF:

Cerebral spinal fluid

DC:

Dendritic cell

HA:

Hemagglutinin

hMPV:

Human metapneumovirus

IAPA:

Influenza-associated pulmonary aspergillosis

IAV:

Influenza A virus

IBV:

Influenza B virus

ICAM-1:

Intracellular adhesion molecule-1

IFN:

Interferon

IFNAR:

IFN-α/β receptor

IFNRG1:

IFN-γ receptor 1

IL:

Interleukin

IL-1β:

Interleukin-1β

IL-6:

Interleukin-6

IL-12:

Interleukin-12

IL-17:

Interleukin-17

IL-18:

Interleukin-18

IL-22:

Interleukin-22

IL-23:

Interleukin-23

IPA:

Invasive pulmonary aspergillosis

IRF:

IFN-regulatory factor

IRGs:

Interferon-regulated genes

ISGs:

Interferon-stimulated genes

JAK-STAT:

Janus kinase-STAT

LPS:

Lipopolysaccharide

LTA:

Lipoteichoic acid

MAVS:

Mitochondrial antiviral signaling proteins

MHC:

Major histocompatibility complex

NA:

Neuraminidase

NF-κB:

Nuclear factor 'kappa-light-chain-enhancer' of activated B-cells

NK-Cell:

Natural killer cell

NOD:

Nucleotide-binding oligomerization domain

NLR:

NOD-like receptor

NP:

Nucleoprotein

NS1:

Nonstructural protein 1

NS1ABP:

Nonstructural-1A binding protein

PAMP:

Pathogen associated molecular pattern

pDC:

Plasmacytoid dendritic cell

PKR:

Protein kinase RNA-regulated

PRR:

Pathogen recognition receptor

RdRp:

RNA-dependent RNA polymerase

RIG-I:

Retinoic acid-inducible gene 1

RLR:

RIG-I-like receptor

RSV:

Respiratory syncytial virus

RNA:

Ribonucleic acid

dsRNA:

Double strand RNA

SARS-CoV-2:

Severe acute respiratory syndrome coronavirus-2

ssRNA:

Single strand RNA

STAT:

Signal transducer and activator of transcription

STING:

Stimulator of interferon genes

TLR:

Toll-like receptor

TNF-α:

Tumor necrosis factor-α

TH17:

Helper T-17T-cell

TREGS :

Regulatory T-cells

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    Kevin Roe

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Roe, K. Increased Fungal Infection Mortality Induced by Concurrent Viral Cellular Manipulations. Lung 201, 467–476 (2023). https://doi.org/10.1007/s00408-023-00642-6

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