At one end host-evoked inflammatory response aids in combating infectious endophthalmitis, while on another hand, persistent inflammation and infiltration of immune cells can lead to host-induced damage which eventually result in disruption of the normal visual axis and vision loss.
6,56 In our mouse models, we observed an upregulated cytokine/chemokine response, as well as an increase in cellular infiltration in the vitreous cavity, accompanied by retinal folding/detachment and significant damage to retinal architecture. Infiltrating PMNs are considered as the first line of defense during infectious endophthalmitis and are one of the main cell types involved in the initiation of an inflammatory response. During ocular infections, residential retinal innate immune cells, such as the microglia
59 and the Müller glia,
60 secrete neutrophil chemotactic factors that attract PMNs to the site of infection. We observed that CA infection leads to a significant increase in the infiltration of PMNs into the retina. Our comparative analyses revealed that B6 mice had increased PMN infiltration than BALB/c which coincided with higher levels of neutrophil chemoattractant, CXCL2/MIP2, in B6 versus BALB/c mice. It is well known that mouse genetic background plays an important role in orchestrating immune responses with studies showing that B6 mice generate Th1-response whereas BALB/c mice favor Th2-response.
61–63 The effect of inflammatory cytokines on Th1/Th2 skewing has been shown to play a protective or detrimental role against pathogens.
64 For example, TNFα has been shown to promote macrophage activation in Th1 environment leading to protection, while, in the presence of Th1+Th2 response it causes necrosis during Mycobacterial infection.
65 Similarly, different dosages of
Leishmania major have been shown to skew the Th2 versus Th1 response in Th2-dominant BALB/c mice leading to its susceptibility or resistance.
66 These studies indicate that the type of inflammatory cytokines and infectious dosage of pathogens modulate the Th1/Th2 response leading to susceptibility and resistance toward infections. Similarly, BALB/c mice have been reported to fail in facilitating bacterial killing in comparison to C57BL/6 mice in a murine model of septic peritonitis, which is attributed to their differential cytokine response.
62 Our data showing lower fungal burden and delayed disease progression in B6 mice in contrast to BALB/c mice, could be attributed to increased PMN infiltration and production of inflammatory mediators. Therefore, these strain-specific differences in the microenvironment may alter the Th1/Th2 milieu and ultimately susceptibility to the infection in CA endophthalmitis. Reduced neutrophil chemotaxis and infiltration have been shown to contribute in the disease progression in various infection models.
67–69 In one of our recent studies, we also demonstrated that depletion of PMNs increases mice susceptibility to
Aspergillus endophthalmitis, which results in severe ocular pathology.
70 Inflammation and infiltrating immune cells work as a double-edged sword: they help in controlling infection but can also contribute to damaging tissue.
49,61,71,72 The visual function of the retina is highly susceptible to the host-induced inflammatory damage. In our current study, we observed a significant decline in ERG response with Candida infection by 12 hpi and nearly a total loss of visual function just in 24 hours of infection. Although we observed differences in disease pathology in BALB/c and B6 mice, the overall loss of visual function was similar in these mice.