One notable inclusion in this category is MAN2B2-CDG, recently recognized as an inborn error of immunity with the first reported patient presenting immunodeficiency, dysmorphic facial features, coagulopathy, and severe developmental delay (39, 41).

MAN2B2 is a mannosidase involved in the second-to-last step of lysosomal degradation of glycoproteins, the cleavage of the α1,6-mannose residue of Man2GlcNAc1 to generate Man1GlcNAc1 ( Figure 2 ). MAN2B2 deficiency dysregulate the deglycosylation and monosaccharide recycling process, leading to the accumulation of terminal 1,6-mannose-bearing Man2GlcNAc1 and defective protein N-glycosylation (41). The clinical manifestations in the first reported patient were recurrent vasculitis, arthritis, and infections. The patient showed decreased counts of naïve cytotoxic and helper T cells, but increased effector memory T cells, meaning a skewed T cell repertoire. There was also low T cell proliferation and undetectable T cells receptor excision circles (TRECs), highlighting lack of T cell maturation. Additionally, B cell lymphopenia with elevated circulating plasmablasts and dysreactive B cells were detected, along with low IgM and IgA levels and high IgE, which are not a typical feature of CDG-related immunodeficiencies, but may explain autoimmunity ( Supplementary Table 1 ) (41). There were no investigations directly linking MAN2B2 deficiency to the observed immune alterations. Nevertheless, the intercellular adhesion molecule 1 (ICAM1) adhesion protein and lysosomal associated membrane protein 2 (LAMP2), known to play a critical role in T cell regulation (42, 43), are underglycosylated in the patient’s fibroblasts (41), suggesting the protein functions are affected and deserving further studies to address the exact mechanisms. Yet, a newly reported Chinese patient presented normal immune parameters alongside presentation of several malformations (44), which raises the question if MAN2B2-CDG is as a condition with major immunological involvement or a disorder with infrequent immunological occurrences.

Due to the small number of MAN2B2-CDG patients described, there is a lack of information regarding treatment response. One patient receiving immunoglobulin replacement therapy initiated at two years of age failed to improve the immune manifestations. Yet, hematopoietic stem cell transplantation (HCST) at the age of five years restored T cell count and function, antibodies production and resolved the infection episodes (41).

EXTL3- and PGM3-CDG are the CDG included in the category of combined immunodeficiencies with syndromic features, presenting variable immunophenotypes ranging from isolated infections to severe immunodeficiency, including neurodevelopmental and skeletal defects. EXTL3-CDG compromises the glycosaminoglycan and the heparan sulfate biosynthesis by affecting GlcNAc transfer ( Figure 2 ). Alterations in the length and content of heparan sulfate are known to disbalance biological mechanisms and signaling pathways. On the one hand, heparan sulfate has a critical role in the binding and directing cells and growth factors during thymic epithelial cell differentiation and hematopoietic progenitor cell expansion (45–47). Consistently, EXTL3-CDG immunodeficiency was shown to majorly derive from defects in early T cell development (48). On the other hand, heparan sulfate alterations increase fibroblasts growth factor receptor signaling by increasing ligand binding, concordant with previously reported mechanisms of skeletal dysplasia. Besides, decreased STAT5 phosphorylation in response to IL-2 and IL-7 was found in patient immune cells indicative of impaired cellular responses (48). In addition to patients with variable immunophenotypes, some patients (n = 3/16) have no apparent immune issues (49). The cause of EXTL3-CDG clinical variability has been suggested to be related to the associated genetic variants. Variants affecting the EXT domain seem to be related with skeletal defects whilst variants affecting the transferase activity resulting in defective glycosaminoglycans modifications associated with immunophenotypes. However, patients with the same mutation can greatly differ phenotypically (50). Other genetic interactions, gene modifiers or environmental factors are possibly behind the different degrees of immunodeficiency severity (48).

In PGM3-CDG, there is an impairment on the synthesis of UDP-GlcNAc due to the deficient PGM3 activity ( Figure 2 ). This deficiency affects the number and function of different immune cells resulting in repeated dermal and pulmonary bacterial or fungal infections ( Supplementary Table 1 ). These manifestations seem to mainly derive from altered signaling pathways disbalancing the immune response towards a Th2 profile (51, 52). Specifically, in PGM3-CDG, the N- and O-glycosylation of T cells is impaired. Decreased O-GlcNAcylation disrupts NFAT function (53) and NF-κB transcriptional activation (54) whilst defective N-glycosylation of the gp130 protein impairs STAT3-mediated signaling (55), which negatively interferes with T cell proliferative capacity and cytokine production (53, 55, 56). This results in abnormal levels of various cytokines (e.g., IL-6, IL-17, IL-27, and granulocyte colony stimulating factor - GCSF) which impairs cytokine-mediated immune responses, such as memory cell differentiation, and elevates IgE associated allergy and atopy – a hallmark of PGM3-CDG (55, 57). The dysregulation of the metabolic profile of PGM3-deficient cells was also proposed as a contributing factor to the immune issues (58).

HSCT has been successfully performed as a treatment for EXTL3-CDG and PGM3-CDG immunodeficiency recovering the normal T cell development in these patients and is already approved for PGM3-CDG (59, 60).

ALG12-, ATP6AP1-, and MOGS-CDG fall within as the category of predominantly antibody deficiencies since all of them present hypogammaglobulinemia, with low IgG levels. Despite this common immune hallmark, each disorder presents distinct clinical features. ALG12- and MOGS-CDG are multi-systemic disorders with development delays, hypotonia, dysmorphism and various organ-related manifestations, while ATP6AP1-CDG mainly presents an immunodeficient phenotype with liver involvement.

Defects in either ALG12 or MOGS compromise N-glycan biosynthesis (61, 62). ALG12 is a mannosyltransferase responsible for adding the eighth mannose to the lipid-linked oligosaccharide precursor, whereas MOGS is a glucosidase that catalyzes the trimming of the first glucose residue from the Glc3-Man9-GlcNAc2 precursor ( Figure 2 ). In turn, ATP6AP1 is the first accessory subunit of the proton transporting vacuolar (V)-ATPase pump ( Figure 2 ) whose defects compromises both N-glycosylation and mucin type O-glycosylation (63, 64). This leads to deficient antibody glycosylation that decrease their thermal stability, resistance to unfolding and proteolytic cleavage (65) and interferes with their function by affecting antibody binding to Fc receptors (66, 67). Consequently, this likely contributes to the genesis of the antibody deficiency, inflammatory episodes and absent responses to vaccines observed in ALG12-, MOGS-, and ATP6AP1-CDG. The hypogammaglobulinemia reported in ALG12- and MOGS-CDG patients (68, 69) translates into propensity for recurrent and severe bacterial infections due affected antibody-mediate immune processes. Altered lymphocyte counts and dysfunction are also common even though the causative mechanisms are still not understood ( Supplementary Table 1 ). It has been described that MOGS-CDG patients have resistance to glycosylation-dependent enveloped viruses. This can be explained by the fact that these viruses often hijack the host glycosylation machinery to modify their viral proteins required for viral replication and cellular entry (70, 71). Yet, a recent report challenges this hypothesis, by identifying several infections by enveloped viruses in two patients (62, 72–74).

Considering that these CDG belong to the category of inborn error of immunity mainly associated with decreased levels of circulating Igs, some ALG12-CDG patients have been treated with Ig infusions with apparent no success (61, 75). Similar therapeutic strategies to control immune manifestations in MOGS- or ATP6AP1-CDG are not known in the literature. Nevertheless, Ig infusions are widely recommended to this category of inborn error of immunity.

Magnesium transporter 1 (MAGT1) deficiency has been only recently recognized as a CDG after the unveiling that MAGT1 besides function as Mg²⁺ transporter is a critical accessory protein for immune cell N-glycosylation (76–78). Clinically, most patients present a disease named X-linked MAGT1 deficiency with increased predisposition to Epstein-Barr virus (EBV) infection and N-linked glycosylation defects (XMEN) (76, 78–80), having increased susceptibility to viral respiratory, oral, and skin infections and, in some cases, autoimmune conditions and alterations in vaccination responses ( Supplementary Table 1 ). More recently, variations of the MAGT1-CDG phenotype were described with one patient with muscle involvement characterized by myositis with immune infiltrates (81) and two patients with a different neurological phenotype without immune involvement (79). However, the causes of clinical variability are still elusive.

The selective immune dysregulation in MAGT1-CDG with the XMEN phenotype stems from STT3B-dependent glycosylation alterations of immune-related molecules. In fact, MAGT1 is part of the STT3B complex which is a subunit of the OST complex ( Figure 2 ). Therefore, even though the exact mechanisms are not yet understood, the Mg²⁺ transport defect results in incomplete glycosylation of a subgroup of STT3B substrate proteins (77, 79). Namely, among others, defective glycosylation of NKG2D, a regulator of natural killer (NK) and CD8⁺ T cells responsiveness, reduces its stability and membrane expression while increasing its degradation, compromising the anti-viral immune responses (78). The T cells co-stimulator CD28 is also hypoglycosylated, impairing CD28-mediated cell signaling required for immune processes, such as leukocyte activation, movement, apoptosis regulation, cellular adhesion, and adaptive immune responses. Importantly, CD70 underexpression and hypoglycosylation was also found, which predisposes individuals to uncontrolled EBV infection by affecting humoral and cell-mediated immunity in humans through CD27-CD70 impaired signaling, especially important for the control of EBV (78, 82). Ig hypoglycosylation was observed, explaining the hypogammaglobulinemia in about half of the reported patients ( Supplementary Table 1 ) (77). These observations not only support the association of MAGT1 deficiency with CDG but also explain the increased EBV viremia and a higher risk of EBV-related B cell lymphomas and lymphoproliferative disorders which are associated with increased mortality in these patients (83).

Patients with EBV-related malignancies are managed with radio and/or radiotherapy with varying outcomes (76). The use of magnesium supplementation in MAGT1-CDG patients with an XMEN phenotype showed mixed results. While it partially recovered NKG2D expression and reduced persistent EBV infections and likely reduced EBV-associated malignancies in some patients (84), others did not respond to supplementation (85). Alternative therapeutic approaches have been tested. One patient was treated with a MAGT1 messenger RNA with restoration of NKG2D expression and CD8⁺ T and NK cell levels (86). More recently, an ex vivo approach using CRISPR/Cas9 adeno-associated vector able to insert a MAGT1 gene in T lymphocytes or hematopoietic stem and progenitor cells from MAGT1-CDG patients was optimised which recoved NKG2D expression and function in NK and CD8⁺ T cells in an immunodeficient mice (87). These studies bring some hope in developing effective therapeutic options for this CDG.

SLC35C1-, G6PC3-, JAGN1-, and VPS13B-CDG are diseases related to phagocytic cells which, subsequently, manifest with frequent and severe infections, particularly affecting the skin, oral cavity, and respiratory tract ( Supplementary Table 1 ).

SLC35C1 codes for a transporter of GDP-fucose ( Figure 2 ) and SLC35C1 pathogenic variants affect the biosynthesis of selectin ligands and other fucosylated glycoproteins important for leukocyte adhesion (88, 89). Thus, SLC35C1-CDG, also called Leukocyte Adhesion Deficiency type II (LAD-II), shows impairment of leukocyte migration and homing due to decreased expression of selectin ligands, with subsequent propensity for infections (90). The clinical phenotype includes milder intellectual disability, short stature (91–93), and, in severe cases dysmorphia, immunodeficiency, and the Bombay blood type (94, 95). Oral fucose supplementation was found to not only improve the neurological development of SLC35C1-CDG patients, but also reduce the number of recurrent infections and normalize the neutrophil counts. However, fucose supplementation can induce autoimmunity, as the appearance of fucosylated neoantigens on the cells may induce the production of autoantibodies (94, 96).

Genetic variants in G6PC3, JAGN1, and VPS13B affect the number and function of neutrophils (rather than their migration) which consequently cause different forms of severe congenital neutropenia (SCN). While G6PC3- and JAGN1-CDG show persistent neutropenia and bone marrow defects, VPS13B-CDG presents intermittent decreased neutropenia with normal bone marrow development and cellularity ( Supplementary Table 1 ). Besides, G6PC3-CDG and VPS13B-CDG patients present Dursun and Cohen syndrome, respectively, whereas JAGN1-CDG presents solely SCN (97, 98). These phenotypes are likely to arise from the distinct roles of these enzymes in the glycosylation process. Specifically, G6PC3 catalyzes the last step of glycogenolysis in the ER ( Figure 2 ), decreasing the levels of glucose and glucose-6-P in the cytoplasm. Additionally, G6PC3-CDG patient neutrophils show truncated, galactose-defective N- and O-glycans (99). JAGN1 is involved in the vesicle-mediated transport in the glycosylation pathway ( Figure 2 ) and its deficiency leads to increased Gal-α-1,3-Gal terminated triantennary glycans and decreased sialylated biantennary glycans (100). VPS13B protein mediates lipid transfer between membranes ( Figure 2 ) and defects in this protein causes Golgi disorganization, hypoglycosylation of early endosome antigen 1 and of lysosome-associated membrane glycoprotein 2, as well as N-glycan maturation defects (101–103).

Even though the direct cause of glycosylation-related pathological effects is still elusive, proposed mechanisms for the multi-factorial neutropenic phenotypes, include increased neutrophil death associated with metabolic dysregulation, ER stress and apoptosis, and decreased levels of respiratory burst, calcium mobilization, and neutrophil survival factor (SERPINB1) (103–106); neutrophil dysfunction with abnormal protein glycosylation impacting neutrophil migration, adhesion and cytotoxicity (101, 105, 107); and bone marrow maturation defects and in some cases myelokathexis (99, 108, 109). Consequently, these defects impact the ability of neutrophils to correctly fight infections.

Besides neutrophils, other immune cells and antibodies can be altered in the CDG included in this category ( Supplementary Table 1 ). In fact, abnormal B cell counts, and function were detected, associated with altered ER homeostasis and aberrant Ig N-glycosylation in a Jagn1 deficient mouse model and patient-derived cells (110). Inflammatory and autoimmune manifestations, especially in G6PC3-CDG include IBD with 16% of prevalence ( Supplementary Table 1 ). It was suggested that IBD prevalence in this CDG could derive from higher and consistent neutrophil activation leading to elevated expression of adhesion molecules, inflammatory cytokines, and reactive oxygen species (111).

Treatment with sodium-glucose cotransporter 2 inhibitors, which inhibit renal glucose reabsorption, improved neutrophil counts and function and reduced the severity of infection episodes in G6PC3-CDG patients (112, 113). On the other hand, GCSF is typically used in neutropenia management but failed to show therapeutic efficacy, despite increasing neutrophil production (112). GCSF treatment also showed poor response when used in patients with JAGN1 mutations and HSCT has been the treatment of choice for JAGN1-CDG (114, 115). Regarding VPS13B-CDG, GCSF can be used to control the neutrophil levels (116, 117).

Although FUT8-CDG has not been yet categorized as an inborn error of immunity, all described patients show strong immunological involvement especially in the lung. FUT8-CDG is caused by genetic variants in fucosyltransferase 8 (FUT8) which catalyzes the transfer of the fucose residue from GPD-fucose to the first GlcNAc residue of N-glycans, known as core fucosylation ( Figure 2 ). Presently, only nine known FUT8-CDG patients exhibit severe multi-organ disease (118–120) with infection and inflammatory events of the lungs and respiratory tract. These immune manifestations are mostly recurrent leading to respiratory failure in severe instances ( Supplementary Table 1 ) (120). The reason for the variable outcomes in FUT8-CDG is still elusive. The lung immune dysfunction observed in FUT8-CDG is likely related to dysregulation of the TGF-β1 receptor. Specifically, studies in Fut8 ^-/- mice show that defects in TGF1-β1 activation and signaling, leading to overexpression of matrix metalloproteinases and downregulation of extracellular matrix proteins, resulting in delayed alveolar epithelial differentiation and the presence of emphysema-like lung abnormalities (121).

Cellularly and biochemically, the few available reports show the occurrence of neutropenia and IgG hypofucosylation in FUT8-CDG. Nevertheless, FUT8-related depletion of core fucosylation has been linked to antibody dysfunction, profound alterations in B and T cells, hypogammaglobulinemia, as well as impaired recognition, assembly, and lipid raft association of pre- and IgG-B cell receptor antigen (122–127). Even though these finding underline a key role of FUT8 in controlling lung immunity and inflammation, further detailed investigations are warranted to: (1) unveil systemic immune response impact, which might become apparent as more patients are diagnosed, and (2) accurately categorize FUT8-CDG as an inborn error of immunity.

Fucose supplementation has been explored for FUT8-CDG with mild improvement of the clinical phenotype in two patients. However, a more noticeable effect may require adjusting the amount of fucose (118). In case of severe respiratory disease, supportive measures like continuous positive airway pressure and tracheostomy have been adopted (118, 120).

PMM2-CDG leads to profound alterations in N-glycosylation, resulting in incomplete glycan chains and truncated lipid-linked oligosaccharides (169). Serum protein analysis reveals decreased tetrasialotransferrin and increased disialotransferrin and asialylated isoforms, aiding PMM2-CDG screening (34). Besides transferrin, many liver proteins show N-glycan defects which contribute a range of symptoms and complications. While few studies explore patient-derived cells, altered mannosylation and mannose-terminal glycans are evident. Despite the reduced mannose incorporation in fibroblasts from PMM2-CDG patients (169), an intriguing report showcased hypermannosylation of monocytes in two patients (170). The intricate landscape of oligomannosidic glycans showed a reduction in long glycans (171), but an increase in short high mannose glycans, such as Man3GlcNAc2 and Man4GlcNA2 in several patients (171–173).

Other glycan alterations include low levels of a non-mannosylated tetrasaccharide - Neu5Acα2,6Galβ1,4-GlcNAcβ1,4GlcNAc (171, 172) and elevation of endogenous glycosphingolipids in patient fibroblasts (174). Aberrant sialylation is observed in PMM2-CDG patients. Particularly, low sialylation was observed in platelets, fibroblasts, and B cells of patients (174–177), contrasting with high sialylation seen in monocytes of three patients (170).

Overall, PMM2-CDG patients have a distinctive glycan profile characterized by inferior number of N-glycosylation sites, incomplete N-glycans with terminal mannose residues, reduced sialylation, and increased expression of glycosphingolipids. This multifaced glycan profile contributes to molecular interaction and cell recognition, underpinning the disease’s symptoms and complications.

The altered glycan profile of PMM2-CDG patients could be directly or indirectly implicated in the immunological manifestations reported in these patients ( Table 1 ). Firstly, compromised glycosylation indicates a disruption in the recognition and response triggering of ligands by immune receptors. For example, glycosylation of Toll-like receptors and other pathogen recognition receptors is pivotal in the recognition and binding of pathogen structural components in these heavily glycosylated structures, affecting and conditioning the optimal functioning of these receptors (178–182). This means that, in a disease as PMM2-CDG, where hypoglycosylation is prevalent, the impaired general glycosylation caused by this defect early in the N-glycosylation pathway could compromise the effective recognition of threats by immune receptors and the overall immunological response in these patients, leading to a possibly higher susceptibility to recurrent and severe infections in PMM2-CDG patients.

Moreover, increased truncated surface N-glycans have been associated with chronic gastrointestinal inflammation, such as IBD (183). One of the mechanisms known to be associated with IBD and other autoimmune diseases severity is a deficiency in branched N-glycans in the mucosal T lymphocytes, which has been associated with mutations in the MGAT5 gene, leading to a hyperimmune response (184, 185) With a mutation in the PMM2 enzyme, an early defect in the N-glycosylation pathway also leading to truncated N-glycans, a decrease in complex and branched glycans, and a known heterogenous clinical phenotype in PMM2-CDG, it is possible that the gastrointestinal inflammatory events observed in patients share the same mechanisms as IBD and other autoimmune diseases. The study of mannose in the regulation of immune processes showed that increased levels of mannosylated glycans might play a role in inducing inflammatory autoimmune-type responses, such as in systemic lupus erythematosus (SLE) (186). The higher abundance of mannosylated glycans has been associated with SLE through increased γδ T lymphocyte development and infiltration into the kidneys (187, 188). Additionally, the alteration of terminal sialic acid levels observed in PMM2-CDG might point towards the dysregulation of inflammation and autoimmunity processes (189, 190). In fact, hyposialylation of immunoglobulins has been linked to autoimmune pathologies, such as granulomatosis, chronic inflammatory demyelinating polyneuropathy and rheumatoid arthritis (189). Besides, sialic acid has been shown to have an important role in regulating the activation, proliferation, modulation, and orientation of several immune cells, including dendritic cells, T and B cells (189, 191). Although these observations may contribute to the understanding of infections, inflammatory manifestations in tissues, or even unexplained febrile illness that occurs in PMM2-CDG, caution should be taken while drawing definitive conclusions due to glycan heterogeneity between patients (170).

The nuanced interplay between host and pathogen constitutes a fundamental facet of the infection. Glycans are known pivotal mediators for pathogen recognition and the cell glycoprofile serves as critical determinants of infection outcomes. The glycans expressed in some PMM2-CDG patient derived tissues have been elucidated, and described above, which allows us to have a general overview of the PMM2-CDG glycan profile.

Altered glycans in the PMM2-CDG host may also indicate higher susceptibility to binding and invasion by microorganisms across diverse cells and tissues, given the existence of a thinner and less dense glycocalyx - a glycan-rich structure which protects cells and tissues from aggression (192). The disbalance of the glycocalyx exposes novel glycan epitopes, such as altered patterns of sialylation and exposed mannose, thereby providing pathogens with potential attachment and invasion sites (192).

Figure 4 illustrates a comparative analysis between the N-glycosylated plasma membrane of a healthy individual, with the hypothetical model of a PMM2-CDG patient plasma membrane, constructed based on the known main characteristics of these patients’ glycan profile. Within this context, we highlight some potential host-pathogen interactions, where microorganisms infecting PMM2-CDG patients gain advantages by recognizing specific glycan structures or having facilitated access to otherwise protected sites.

Some PMM2-CDG patients exhibit increased synthesis of several glycosphingolipids (174), notably globotriaosylceramide (Gb3), a sphingolipid that serves as the canonical receptor of Shiga toxin, which is a very potent bacterial toxin that can lead to hemolytic and uremic syndrome and, in most severe cases, death (193, 194). This toxin is produced by Shigella dysenteriae and by Shiga toxin producing E. coli, such as E. coli O157:H7 (193). Gb3 also acts as the binding site for lipid-binding adhesins, such as PapG (E. coli), LecA (Pseudomonas aeruginosa) and SadP (Streptococcus suis) (195–197). All these adhesins and Shiga toxin are identified as mediators in the pathogenic infection process. Thus, the exposure of Gb3 in PMM2-CDG patients can increase susceptibility to infection by these pathogenic bacteria through these intermediaries, as illustrated in Figure 4 . An increased expression of glycosphingolipids, especially Gb3, in PMM2-CDG patients, might render them not only more susceptible to a broader range of infections but also make organs and tissues, typically less affected by microorganisms’ infection, more vulnerable.

Sialic acid, known to facilitate infection by many viruses and bacteria, such as Influenza viruses or Haemophilus influenza bacteria, also serves as an energy source for commensal microorganisms (198, 199). Abnormal sialylation can eventually disrupt the microbiota balance, creating a more favorable environment for growth and persistence of pathogenic microorganisms. This imbalance can grant direct access to the host epithelium or availability of secreted products, with Clostridium difficile being the bacterial infection mostly associated with gut dysbiosis ( Figure 4 ) (200, 201). Additionally, some bacteria have developed strategies to eliminate sialic acid residues to bypass its protective roles within the intricate glycocalyx network. Employing this strategy, the bacteria uncover novel adhesin binding sites and gain closer proximity to the cell membrane to infect the host. Notable examples include glycosyl-hydrolases NanA of Streptococcus pneumoniae, and NanH ( Figure 4 ) and ChiA of Salmonella typhimurium, which degrade terminal sialic acid residues (202–204). In the case of PMM2-CDG patients who present lower levels of sialylation, pathogenic bacteria may find the infection process easier because they do not need to use their neuraminidase to access internal glycan epitopes to initiate their adhesion process. Therefore, the abnormal sialic acid profile in PMM2-CDG might contribute and indicate a disrupted microbiota, creating a conducive environment for pathogenic infections.

The reduction of longer-high mannose glycans and high abundance of short high-mannose glycans observed in PMM2-CDG may also have implication in the recognition by pathogen’s critical adhesion factors needed for the colonization and infection. In Table 2 , we present several adhesion factors that are known to be mannose sensitive. FimH, a well-studied lectin-like mannose-binding adhesins, is expressed in many bacteria of the Enterobacteriaceae family, such as Escherichia coli, Salmonella enterica and Klebsiella pneumoniae (212–215). Specifically, FimH from E. coli has a striking and versatile binding capability interacting with a wide range mannose–containing glycans, exhibiting a higher affinity for oligomannose-3 and oligomannose-5 structures with Manα-(1,3) branches (216). These specific glycans, such as Man3GlcNAc2, appear to be more prevalent in PMM2-CDG patients ( Figure 4 ). Another mannose-related adhesion factor is CsuA pilus of Acinetobacter baumannii which has been confirmed to contribute to biofilm formation and adherence to the respiratory epithelium (211). In summary, an aberrant glycosylated environment with an increased prevalence of terminal mannose-containing glycans can significantly benefit these microorganisms, by providing binding sites in close proximity to the cell surface and granting an advantage over host defenses.

Although these host glycosylation-based host-pathogen interactions are recognized as contributors to infection, discerning the exact impact of the glycosidic alterations in PMM2-CDG patients on their susceptibility to infections remains challenging. More information on the glycan profiling of patients’ epithelial tissues would provide more accurate information to formulate target research questions and exploratory studies based on available data concerning microorganisms infecting PMM2-CDG patients.