Technologies for Proteome-Wide Discovery of Extracellular Host-Pathogen Interactions

Table 1

Overview of the main high throughput approaches utilized to detect ePPI between pathogens and their respective hosts and relevant examples discussed thorough the text.

Pathogen	Identification method	Main findings	References
Human cytomegalovirus (hCMV)	Biochemical and MS	PDGFRα identified as a high affinity cell surface receptor for the CMV gHgLgO protein complex	[21]
Herpes simplex viruses (HSVs)	Biophysical	Secreted and plasma membrane-expressed glycoprotein G targets a specific set of human chemokines with high affinity	[22]
Human immunodeficiency virus type 1 (HIV)	Monoclonal antibodies	CD4 identified as the receptor for HIV infection of T cells	[23, 24]
Rhinovirus	Monoclonal antibodies	ICAM-1 as the common entry receptor for most rhinovirus serotypes	[25, 26]
Plasmodium falciparum	AVEXIS	BASIGIN identified as the cell-surface receptor that mediates erythrocyte infection	[27]
Human adenoviruses	Extracellular human protein microarrays	Elucidation of the extracellular interactome of adenovirus-encoded immunomodulatory proteins	[28]
Pseudomonas aeruginosa	Extracellular pathogen protein microarrays (NAPPA)	Screening of patient sera against all P. aeruginosa extracellular proteins. 12 proteins identified as potent antigens	[29]
Varicella zoster virus (VZV)	Extracellular pathogen protein microarrays (NAPPA)	Identification of 18 extracellular viral proteins that promote humoral responses upon screening of the entire VZV proteome	[30]
Streptococcus	Extracellular pathogen protein microarrays	Identification of new streptococcal proteins that interact with fibronectin, fibrinogen, and C4BP factors	[31]
Hepatitis delta virus LHDAg antigen	Plasma membrane microarrays (MPA)	150 candidate interactions identified between viral antigen and plasma membrane proteins	[32]
Simian virus 40 (SV40)	Plasma membrane microarrays (MPA)	99 candidate interactions between whole particles and plasma membrane proteins identified	[32]
Vaccinia virus (VACV)	TRICEPS (MS)	7 candidate cell surface binding partners identified for VACV	[33]
Viral pathogens	Computational studies	Insights into global principles of virus-host PPI networks	[15–18, 34–36]
Hepatitis C virus (HCV)	cDNA libraries	CD81, Claudin-1, and Occludin as cell surface receptors and some of the players involved in HSV internalization	[37–39]
Adenovirus and coxsackievirus B	Monoclonal antibodies and cDNA libraries	CAR identified as a common entry receptor for adenovirus 2/5 and coxsackievirus B	[40]
Sindbis virus	siRNA screens	NRAMP as cell surface receptor for entry into Drosophila cells	[41]
Murine norovirus	CRISPR/Cas9	CD300lf identified as a cell surface receptor that determines virus tropism	[42]
Bacterial distending toxins (E. coli)	Haploid cell screens	Sphingomyelin synthase 1 and the putative G protein-coupled receptor TMEM181 identified as toxin receptors	[43, 44]
Clostridium difficile and perfringens toxins	Haploid cell screens	Lipolysis-stimulated lipoprotein and the low-density lipoprotein receptor-related protein 1 identified as the receptors for the bacterial toxins, respectively	[45, 46]
Ebola virus	Haploid cell screens	HOPS proteins and the Niemann-Pick C1 (NCP1) transporter identified as endosomal receptors that mediate cytosol access	[47]
Lassa virus	Haploid cell screens	LAMP1, lysosomal-associated membrane protein 1 identified as an essential host factor mediating virus release to cytosol	[48]
Adeno-associated virus (AAV) serotype 2	Haploid cell screens	46 cell host factors identified, including heparin sulfate proteoglycan biosynthesis and intracellular transport genes. The immunoglobulin domain-containing transmembrane protein KIAA0319L identified as AAV receptor	[49]
Plasmodium falciparum	Population genomics analysis	P. falciparum EBL-1 protein binds to the erythrocyte receptor glycophorin B, a highly polymorphic gene in malaria-endemic regions	[50]
Streptococcus	Phage display	19 bacterial proteins identified as potential fibronectin-binding proteins	[51]
Fusobacterium nucleatum	Transposon-based mutant libraries	The bacterial protein Fap2 binds to the receptor TIGIT and downregulates NK-mediated killing of tumor cells	[52]

AVEXIS, Avidity-based extracellular interaction screen; NAPPA, nucleic-acid programmable protein array; MPA, microfluidic-based comprehensive protein array; CRISPR, clustered regularly interspaced short palindromic repeat; MS, mass spectrometry; PPI, protein-protein interaction.